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Huang L, Sun X, Zuo Q, Song T, Liu N, Liu Z, Xue W. A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines. Mater Today Bio 2025; 31:101523. [PMID: 39935894 PMCID: PMC11810845 DOI: 10.1016/j.mtbio.2025.101523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/18/2025] [Accepted: 01/24/2025] [Indexed: 02/13/2025] Open
Abstract
Bromodomain-containing protein 4 (BRD4) is a key protein that drives the development of malignant melanoma and is closely associated with the ferroptosis signaling pathway. Degradation of BRD4 can downregulate the expression of ferroptosis-related genes such as GPX4, thereby promoting tumor-specific ferroptosis. Therefore, targeting BRD4 for degradation is a promising strategy for inhibiting tumor growth. We constructed a PROTAC drug-based tumor antigen capture system to protect the activity of antigen-presenting cells (APCs) and promote antigen capture. The selected PROTAC drug (ARV-825) can specifically degrade BRD4 without harming immune cells. Specifically, magnetic nanoclusters (MNC) coated with calcium-doped manganese carbonate (Ca/MnCO3), were used to load PROTAC drug (ARV-825) and anti-PD1, forming the MNC@Ca/MnCO3/ARV/anti-PD1 system. ARV-825 can specifically degrade BRD4 and GPX4, significantly inducing ferroptosis in tumor cells and releasing tumor-associated antigens. The MNC@Ca/MnCO3 particles, with their large specific surface area, adsorbed the tumor antigens, preventing antigen loss and enhancing antigen presentation. Additionally, Mn2+ served as an adjuvant to promote the maturation and cross-presentation of APCs. Together with the PD1 antibody, this further enhanced the anti-tumor response of the in situ tumor vaccine and reversed the suppressive immune microenvironment. This antigen capture system provides a novel strategy to improve the anti-tumor efficacy of in situ tumor vaccines.
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Affiliation(s)
- Linghong Huang
- Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China
- Department of Urology, Guangdong Provincial Key Laboratory of Urological Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510230, China
| | - Xinyuan Sun
- Department of Urology, Guangdong Provincial Key Laboratory of Urological Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510230, China
| | - Qinhua Zuo
- Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China
| | - Ting Song
- Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China
| | - Ning Liu
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 5106323, China
| | - Zonghua Liu
- Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China
| | - Wei Xue
- Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China
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Qin H, Li Z, Wu J, Liu X, Wang R, Xu J, Zhu X. Diclofenac Enhances the Response of BRAF Inhibitor to Melanoma Through ROS/p38/p53 Signaling. Clin Exp Pharmacol Physiol 2025; 52:e70022. [PMID: 39788129 DOI: 10.1111/1440-1681.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025]
Abstract
BRAF inhibitors (BRAFi) represent a cornerstone in melanoma therapy due to their high efficacy. However, the emergence of resistance causes a significant challenge to their clinical utility. This study aims to investigate the potential of diclofenac as a sensitizer for BRAFi therapy in melanoma and to elucidate its underlying mechanism. BRAFi-acquired resistant melanoma cell lines SK-MEL-5R and A375R were established and treated with diclofenac in combination with BRAFi PLX4032. Cell viability was assessed using the MTT assay, cell proliferation was determined by crystal violet staining, cell apoptosis was evaluated by flow cytometry, and intracellular ROS levels were measured using the DCFH-DA probe-labeled and flow cytometry. Mitochondrial membrane potential was assessed by JC-1 staining and flow cytometry, and protein expression levels were detected by western blotting. Our results demonstrated that diclofenac significantly augmented the cytotoxicity of PLX4032 and enhanced its ability to induce apoptosis in SK-MEL-5R and A375R cells. Diclofenac treatment led to the release of intracellular reactive oxygen species (ROS), consequently reducing transmembrane potential, promoting mitochondrial apoptosis, and activating the ROS downstream p38/p53 signaling pathway. Pretreatment with N-acetylcysteine significantly reversed the sensitizing effect of diclofenac on PLX4032 in SK-MEL-5R cells. These findings suggested that diclofenac sensitized BRAFi-resistant melanoma cells to BRAFi by increasing ROS release and activating p38/p53 signaling pathway. Diclofenac might serve as a promising adjunct therapy to overcome BRAFi resistance in melanoma treatment.
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Affiliation(s)
- Haihong Qin
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
| | - Zheng Li
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
| | - Jinfeng Wu
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
| | - Xiao Liu
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
| | - Ruilong Wang
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
| | - Jinhua Xu
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
| | - Xiaohua Zhu
- Department of Dermatology, Fudan University Huashan Hospital, Shanghai, China
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3
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Chang J, Shin K, Lewis JM, Suh HW, Lee J, Damsky W, Xu S, Bosenberg M, Saltzman WM, Girardi M. Enhanced Intratumoral Delivery of Immunomodulator Monophosphoryl Lipid A through Hyperbranched Polyglycerol-Coated Biodegradable Nanoparticles. J Invest Dermatol 2025; 145:593-604. [PMID: 39122142 DOI: 10.1016/j.jid.2024.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/26/2024] [Accepted: 07/09/2024] [Indexed: 08/12/2024]
Abstract
Immunomodulatory agents have significant potential to enhance cancer treatment but have demonstrated limited efficacy beyond the preclinical setting owing to poor pharmacokinetics and toxicity associated with systemic administration. Conversely, when locally delivered, immunomodulatory agents require repeated administration to optimize immune stimulation. To overcome these challenges, we encapsulated the toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) within hyperbranched polyglycerol-coated biodegradable nanoparticles (NPs) engineered for gradual drug release from the NP core, resulting in a more persistent stimulation of antitumor immune responses while minimizing systemic side effects. In a model of malignant melanoma, we demonstrate that hyperbranched polyglycerol-NP encapsulation significantly improves the antitumor efficacy of MPLA by enhancing its ability to remodel the tumor microenvironment. Relative to free MPLA, hyperbranched polyglycerol-coated NP-encapsulated MPLA significantly increased the NK cell- and cytotoxic T-cell-mediated antitumor immune response and tuned the tumor-draining lymph nodes toward a T helper 1 response. Furthermore, when combined with local delivery of a chemotherapeutic agent, hyperbranched polyglycerol-NP-MPLA induces the conversion of an immunosuppressive tumor microenvironment to immunogenic tumor microenvironment and significantly improves survival.
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Affiliation(s)
- Jungsoo Chang
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, Connecticut, USA
| | - Kwangsoo Shin
- Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, Connecticut, USA
| | - Julia M Lewis
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Hee Won Suh
- Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, Connecticut, USA
| | - Joohyung Lee
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA
| | - William Damsky
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Suzanne Xu
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Marcus Bosenberg
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA; Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut, USA; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, Connecticut, USA
| | - W Mark Saltzman
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, Connecticut, USA; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA; Department of Chemical & Environmental Engineering, Yale School of Engineering & Applied Science, New Haven, Connecticut, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Michael Girardi
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
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4
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Tompkins AG, Gray ZN, Dadey RE, Zenkin S, Batavani N, Newman S, Amouzegar A, Ak M, Ak N, Pak TY, Peddagangireddy V, Mamindla P, Amjadzadeh M, Behr S, Goodman A, Ploucha DL, Kirkwood JM, Zarour HM, Najjar YG, Davar D, Tatsuoka C, Colen RR, Luke JJ, Bao R. Radiomic analysis of patient and interorgan heterogeneity in response to immunotherapies and BRAF-targeted therapy in metastatic melanoma. J Immunother Cancer 2025; 13:e009568. [PMID: 39939139 PMCID: PMC11822426 DOI: 10.1136/jitc-2024-009568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 01/21/2025] [Indexed: 02/14/2025] Open
Abstract
Variability in treatment response may be attributable to organ-level heterogeneity in tumor lesions. Radiomic analysis of medical images can elucidate non-invasive biomarkers of clinical outcome. Organ-specific radiomic comparison across immunotherapies and targeted therapies has not been previously reported. We queried the UPMC Hillman Cancer Center registry for patients with metastatic melanoma (MEL) treated with immune checkpoint inhibitors (ICI) (anti-programmed cell death protein-1 (PD-1)/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (ipilimumab+nivolumab; I+N) or anti-PD-1 monotherapy) or BRAF-targeted therapy. The best overall response was measured using Response Evaluation Criteria in Solid Tumors V.1.1. Lesions were segmented into discrete volume-of-interest with 400 radiomics features extracted. Overall and organ-specific machine-learning models were constructed to predict disease control (DC) versus progressive disease (PD) using XGBoost. 291 patients with MEL were identified, including 242 ICI (91 I+N, 151 PD-1) and 49 BRAF. 667 metastases were analyzed, including 541 ICI (236 I+N, 305 PD-1) and 126 BRAF. Across cohorts, baseline demographics included 39-47% women, 24%-29% M1C, 24-46% M1D, and 61-80% with elevated lactate dehydrogenase. Among ICI patients experiencing DC, the organs with the greatest reduction were liver (-66%±8%; mean±SEM) and lung (-63%±5%). For patients with multiple same-organ target lesions, the highest interlesion heterogeneity was observed in brain among patients who received ICI while no intraorgan heterogeneity was observed in BRAF. 221 ICI patients were included for radiomic modeling, consisting of 86 I+N and 135 PD-1. Models consisting of optimized radiomic signatures classified DC/PD across I+N (area under curve (AUC)=0.85) and PD-1 (0.71) and within individual organ sites (AUC=0.72~0.94). Integration of clinical variables improved the models' performance. Comparison of models between treatments and across organ sites suggested mostly non-overlapping DC or PD features. Skewness, kurtosis, and informational measure of correlation (IMC) were among the radiomic features shared between overall response models. Kurtosis and IMC were also used by multiple organ-site models. In conclusion, differential organ-specific response was observed across BRAF and ICI with within organ heterogeneity observed for ICI but not for BRAF. Radiomic features of organ-specific response demonstrated little overlap. Integrating clinical factors with radiomics improves the prediction of disease course outcome and prediction of tumor heterogeneity.
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Affiliation(s)
- Alexandra G Tompkins
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Zane N Gray
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rebekah E Dadey
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Serafettin Zenkin
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nasim Batavani
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sarah Newman
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Afsaneh Amouzegar
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Murat Ak
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nursima Ak
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Taha Yasin Pak
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Vishal Peddagangireddy
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Priyadarshini Mamindla
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mohammadreza Amjadzadeh
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sarah Behr
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Amy Goodman
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | | | - John M Kirkwood
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Hassane M Zarour
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yana G Najjar
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Diwakar Davar
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Curtis Tatsuoka
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rivka R Colen
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jason John Luke
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Riyue Bao
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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5
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Nie L, Ma J, Yu Y, Tao Y, Song Z, Li J. Exosomes as carriers to stimulate an anti-cancer immune response in immunotherapy and as predictive markers. Biochem Pharmacol 2025; 232:116699. [PMID: 39647605 DOI: 10.1016/j.bcp.2024.116699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/26/2024] [Accepted: 12/03/2024] [Indexed: 12/10/2024]
Abstract
During this era of rapid advancements in cancer immunotherapy, the application of cell-released small vesicles that activate the immune system is of considerable interest. Exosomes are cell-derived nanovesicles that show great promise for the immunological treatment of cancer because of their immunogenicity and molecular transfer capacity. Recent technological advancements have enabled the identification of functional functions that exosome cargoes perform in controlling immune responses. Exosomes are originated specifically from immune cells and tumor cells and they show unique composition patterns directly related to the immunotherapy against cancer. Exosomes can also deliver their cargo to particular cells, which can affect the phenotypic and immune-regulatory functions of those cells. Exosomes can influence the course of cancer and have therapeutic benefits by taking part in several cellular processes; as a result, they have the dual properties of activating and restraining cancer. Exosomes have tremendous potential for cancer immunotherapy; they may develop into the most powerful cancer vaccines and carriers of targeted antigens and drugs. Comprehending the potential applications of exosomes in immune therapy is significant for regulating cancer progression. This review offers an analysis of the function of exosomes in immunotherapy, specifically as carriers that function as diagnostic indicators for immunological activation and trigger an anti-cancer immune response. Moreover, it summarizes the fundamental mechanism and possible therapeutic applications of exosome-based immunotherapy for human cancer.
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Affiliation(s)
- Lili Nie
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China
| | - Jingru Ma
- Department of Clinical Laboratory, the Second Hospital of Jilin University, Changchun, China
| | - Yang Yu
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China
| | - Ying Tao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhidu Song
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China
| | - Jian Li
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China.
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6
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Haibo Z, Tianyun L, Xiaoman C, Xiaoyan H. Cell Senescence-Related Genes as Biomarkers for Prognosis and Immunotherapeutic Response in Colon Cancer. Biochem Genet 2025; 63:124-143. [PMID: 38411939 DOI: 10.1007/s10528-024-10690-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/05/2024] [Indexed: 02/28/2024]
Abstract
Colon adenocarcinoma (COAD) stands out as the most prevalent malignancy diagnosed within the gastrointestinal tract, bearing substantial incidence and mortality rates. The processes of ageing and senescence intricately intertwine with tumorigenesis and immune regulation, concurrently exerting influence on the remodelling of the tumor microenvironment (TME). This phenomenon, in turn, significantly impacts the efficacy of immunotherapeutic interventions. Despite this awareness, the comprehensive understanding of the intricate interplay between cellular senescence and TME in the context of COAD remains elusive. Further inquiry is imperative to comprehensively gauge the relevance of cellular senescence-related genes (CSGs) in the realms of immune infiltration and the prognostication of COAD. Differentially expressed cell senescence-related genes (DE-CSGs) within COAD tumors and normal specimens were discerned through analysis of the TCGA-COAD dataset. Leveraging univariate, LASSO, and multivariate Cox regression analyses, we formulated a prognostic risk signature. Subsequent validation utilised two independent GEO datasets. Furthermore, a nomogram was devised to gauge the prognostic significance of this signature. Additionally, the immune landscape of the Cell Senescence-related Signature (CSS) was characterised using CIBERSORT and TIMER algorithms. The expression levels of CSGs were quantified through RT-PCR in COAD specimens. Drawing upon mRNA expression profiles of 191 DE-CSGs, we successfully established a 9-gene CSS, demonstrating its autonomy as a prognostic determinant for COAD patients. Those assigned high-risk scores exhibited an immunosuppressive phenotype, marked by elevated proportions of resting CD4+memory T cells and macrophages M0, correlating with diminished overall survival. Subsequent analyses uncovered that the amalgamation of CSS with the expression profiles of immune checkpoint key genes effectively predicted patient prognosis. Furthermore, patients with low-risk scores demonstrated a potential association with more favourable therapeutic outcomes in the context of immunotherapy. This study has culminated in the development of a prognostic risk signature grounded in cell senescence-related genes for COAD. We posit that the CSS plays a regulatory role in immune infiltration, emerging as a robust biomarker for prognosis and a predictive indicator for immunotherapeutic responsiveness within the COAD landscape.
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Affiliation(s)
- Zhang Haibo
- Central Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Lan Tianyun
- Central Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Chen Xiaoman
- Central Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Han Xiaoyan
- Central Laboratory, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
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Bowley TY, Ortiz MC, Lagutina IV, Steinkamp MP, Fahy BN, Tawfik B, Harari-Turquie M, Marchetti D. A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain-Liver Metastasis Axis. CANCER RESEARCH COMMUNICATIONS 2025; 5:295-308. [PMID: 39831781 DOI: 10.1158/2767-9764.crc-24-0498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
SIGNIFICANCE This study provides important insights into the relevance of prometastatic CTC:B-cell clusters in melanoma progression, extends the importance of the CTC RPL/RPS gene signature beyond primary metastasis/melanoma brain metastasis driving targeted organ specificity for liver metastasis ("metastasis of metastasis"), and identifies new targets for clinical melanoma metastasis therapies.
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Affiliation(s)
- Tetiana Y Bowley
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Mireya C Ortiz
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Irina V Lagutina
- Animal Models Shared Resource, The University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Mara P Steinkamp
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Bridget N Fahy
- Division of Surgical Oncology and Palliative Medicine, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Bernard Tawfik
- Division of Hematology and Oncology, Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Moises Harari-Turquie
- Division of Hematology and Oncology, Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Dario Marchetti
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
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Nishikiori N, Ohguro H, Watanabe M, Higashide M, Ogawa T, Furuhashi M, Sato T. High-Glucose-Induced Metabolic and Redox Alterations Are Distinctly Modulated by Various Antidiabetic Agents and Interventions Against FABP5/7, MITF and ANGPTL4 in Melanoma A375 Cells. Int J Mol Sci 2025; 26:1014. [PMID: 39940783 PMCID: PMC11817646 DOI: 10.3390/ijms26031014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Hyperglycemia-induced effects on cellular metabolic properties and reactive oxygen species (ROS) generation play pivotal roles in the pathogenesis of malignant melanoma (MM). This study assessed how metabolic states, ROS production, and related gene expression are modulated by antidiabetic agents. The anti-diabetic agents metformin (Met) and imeglimin (Ime), inhibitors of fatty acid-binding proteins 5/7 (MF6) and microphthalmia-associated transcription factor (MITF) (ML329), and siRNA-mediated knockdown of angiopoietin-like protein 4 (ANGPTL4), which affect mitochondrial respiration, ROS production, and related gene expression, were tested in A375 (MM cell line) cells cultured in low (5.5 mM) and high glucose (50 mM) conditions. Cellular metabolic functions were significantly and differently modulated by Met, Ime, MF6, or ML329 and knockdown of ANGPTL4. High glucose significantly enhanced ROS production, which was alleviated by Ime but not by Met. Both MF6 and ML329 reduced ROS levels under both low and high glucose conditions. Knockdown of ANGPTL4 enhanced the change in glucose-dependent ROS production. Gene expression related to mitochondrial respiration and the pathogenesis of MM was significantly modulated by different glucose conditions, antidiabetic agents, MF6, and ML329. These findings suggest that glucose-dependent changes in cellular metabolism and redox status are differently modulated by antidiabetic agents, inhibition of fatty acid-binding proteins or MITF, and ANGPTL4 knockdown in A375 cells.
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Affiliation(s)
- Nami Nishikiori
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Hiroshi Ohguro
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Megumi Watanabe
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Megumi Higashide
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Toshifumi Ogawa
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Masato Furuhashi
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
| | - Tatsuya Sato
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
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9
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Liu L, Hou S, Zhu A, Yan B, Li L, Song D. The prognostic value of circulating tumor DNA in malignant melanoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol 2025; 15:1520441. [PMID: 39896816 PMCID: PMC11782251 DOI: 10.3389/fimmu.2024.1520441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/30/2024] [Indexed: 02/04/2025] Open
Abstract
Background Circulating tumor DNA (ctDNA) is an emerging biomarker in malignant melanoma(MM), and high levels of ctDNA may reflect a higher tumor load. However, its prognostic value for MM receiving immune checkpoint inhibitors(ICI) remains controversial. This meta-analysis aimed to elucidate the prognostic significance of ctDNA in this patient population. Methods We conducted a comprehensive search of the PubMed, Cochrane Library, CNKI, and EMBASE databases, including studies published up to August 15, 2024, to investigate the prognostic impact of ctDNA in MM patients treated with ICI. Using a fixed-effects model, we systematically evaluated the association between ctDNA levels and key survival outcomes, including overall survival (OS) and progression-free survival (PFS). Additionally, funnel plots, Begg's test, and Egger's test were employed to assess potential publication bias. Results Twelve studies from eleven articles, involving a total of 1063 eligible MM patients receiving ICI therapy, were included. The results indicated that patients with detectable ctDNA before initiating ICI therapy had significantly poorer OS (HR = 3.19, 95% CI = 2.22-4.58, P < 0.001) and PFS (HR = 2.08, 95% CI = 1.61-2.69, P < 0.001). Furthermore, the detectability of ctDNA during treatment was also significantly associated with worse OS (HR = 4.57, 95% CI = 3.03-6.91, P < 0.001) and PFS (HR = 3.79, 95% CI = 2.13-6.75, P < 0.001). Conclusions This meta-analysis indicates that in MM patients receiving ICI therapy, detectable and high levels of ctDNA are significantly associated with poorer OS and PFS. Therefore, ctDNA can serve as a diagnostic and stratification tool prior to treatment, as well as an effective indicator for monitoring treatment response and disease progression. Systematic Review Registration www.inplasy.com, identifier INPLASY2024110018.
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Affiliation(s)
- Lei Liu
- Department of Neurology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shufu Hou
- Department of Gastrointestinal Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Aiping Zhu
- Department of Neurology, Shandong Second Provincial General Hospital, Jinan, China
| | - Bing Yan
- Department of Gastrointestinal Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Linchuan Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Dandan Song
- Department of Neurology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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10
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Yakubov R, Kaloti R, Persaud P, McCracken A, Zadeh G, Bunda S. It's all downstream from here: RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma. J Neurooncol 2025:10.1007/s11060-024-04930-w. [PMID: 39821893 DOI: 10.1007/s11060-024-04930-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND The receptor tyrosine kinase (RTK)/Ras/Raf/MEK/ERK signaling pathway is one of the most tumorigenic pathways in cancer, with its hyperactivation strongly linked to the aggressive nature of glioblastoma (GBM). Although extensive research has focused on developing therapeutics targeting this pathway, clinical success remains elusive due to the emergence of resistance mechanisms. OBJECTIVE This review investigates how inhibition of the RTK/Ras/Raf/MEK/ERK pathway alters transcription factors, contributing to acquired resistance mechanisms in GBM. It also highlights the critical role of transcription factor dysregulation in therapeutic resistance. METHODS & RESULTS Findings from key studies on the RTK/Ras/Raf/MEK/ERK pathway in GBM were synthesized to explore the role of transcription factor dysregulation in resistance to targeted therapies, radiation, and chemotherapy. The review highlights that transcription factors undergo significant dysregulation following RTK/Ras/Raf/MEK/ERK pathway inhibition, contributing to therapeutic resistance. CONCLUSION Transcription factors are promising targets for overcoming treatment resistance in GBM, with cotreatment strategies combining RTK/Ras/Raf/MEK/ERK pathway inhibitors and transcription factor-targeted therapies presenting a novel approach. Despite the challenges of targeting complex structures and interactions, advancements in drug development and precision technologies hold great potential. Continued research is essential to refine these strategies and improve outcomes for GBM and other aggressive cancers.
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Affiliation(s)
- Rebeca Yakubov
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ramneet Kaloti
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Phooja Persaud
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Anna McCracken
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Gelareh Zadeh
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
| | - Severa Bunda
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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11
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Yuan W, Qiu Y, Tang Q, Li M, Tang X, Yang T. Identification of IGF2BP2 and long non-coding RNA TUG1 for the prognosis and tumour microenvironment in head and neck squamous cell carcinoma. ACTA OTORHINOLARYNGOLOGICA ITALICA : ORGANO UFFICIALE DELLA SOCIETA ITALIANA DI OTORINOLARINGOLOGIA E CHIRURGIA CERVICO-FACCIALE 2025:1-11. [PMID: 39844758 DOI: 10.14639/0392-100x-n3024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 10/09/2024] [Indexed: 01/24/2025]
Abstract
Objective This study aimed to investigate the role of m6A-related long non-coding RNAs (lncRNAs) in the prognosis and tumour microenvironment of head and neck squamous cell carcinoma (HNSCC). Methods 497 samples from The Cancer Genome Atlas were analysed to identify m6A-related lncRNAs via correlation models. Tripartite regression models, Kaplan-Meier analysis and nomograms were then utilised to assess the prognostic significance of these lncRNAs. Tumour mutation burden and immune cell infiltration analyses were also performed. Moreover, m6A-related lncRNAs expression and relation with IGF2BP2 were confirmed by RT-qPCR. Results The risk model revealed that high-risk scores predicted poorer survival outcomes. The area under ROC curves for predicting 1-, 3-, 5-year survival in the training set were 0.70, 0.68, and 0.64, respectively. Seven key m6A-related lncRNAs showed associations with immune checkpoint molecules, especially CTLA4 and PD-1. Finally, we found that knockdown of TUG1 repressed the expression of IGF2BP2. Conclusions Our results suggest that the m6A-related lncRNA risk model has potential clinical utility in predicting prognosis and immunotherapeutic responses in patients with HNSCC. Identification of candidate compounds for immunotherapy further emphasises the model's relevance in guiding treatment decisions for HNSCC.
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Affiliation(s)
- Wenhui Yuan
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, China
| | - Yuanzheng Qiu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, China
| | - Qinglai Tang
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengmeng Li
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaojun Tang
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Yang
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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12
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Oh D, Hong N, Eun K, Lee J, Cai L, Kim M, Choi H, Jawad A, Ham J, Park MG, Kim B, Lee SC, Moon C, Kim H, Hyun SH. Generation of a genetically engineered porcine melanoma model featuring oncogenic control through conditional Cre recombination. Sci Rep 2025; 15:1616. [PMID: 39794352 PMCID: PMC11724099 DOI: 10.1038/s41598-024-82554-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 12/06/2024] [Indexed: 01/13/2025] Open
Abstract
Melanoma is a serious type of skin cancer that originates from melanocytes. Rodent melanoma models have provided valuable insights into melanoma pathology; however, they often lack applicability to humans owing to genetic, anatomical, physiological, and metabolic differences. Herein, we developed a transgenic porcine melanoma model that closely resembles humans via somatic cell nuclear transfer (SCNT). Our model features the conditional oncogenes cassettes, TP53R167H and human BRAFV600E, controlled by melanocyte-specific CreER recombinase. After SCNT, transgenic embryos developed normally, with the capacity to develop porcine embryonic stem cells. Seven transgenic piglets with oncogene cassettes were born through embryo transfer. We demonstrated that Cre recombination-mediated oncogene activation remarkably triggered the mitogen-activated protein kinase pathway in vitro. Notably, intradermal injection of 4-hydroxytamoxifen activated oncogene cassettes in vivo, resulting in melanocytic lesions resembling hyperpigmented nevi with increased proliferative properties similar to early human melanomas. This melanoma-inducing system, heritably transmitted to offspring, supports large-scale studies. The novel porcine model provides a valuable tool for elucidating melanoma development and metastasis mechanism, advancing translational medicine, and facilitating preclinical evaluation of new anticancer drugs.
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Affiliation(s)
- Dongjin Oh
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
| | - Nayoung Hong
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Insitute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Kiyoung Eun
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Insitute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Joohyeong Lee
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
- Department of Companion Animal Industry, Semyung University, Jecheon, 27136, Republic of Korea
| | - Lian Cai
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
| | - Mirae Kim
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
| | - Hyerin Choi
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
| | - Ali Jawad
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
| | - Jaehyung Ham
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea
| | - Min Gi Park
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Insitute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Bohye Kim
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Republic of Korea
| | | | - Changjong Moon
- Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Republic of Korea
| | - Hyunggee Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
- Insitute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
| | - Sang-Hwan Hyun
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea.
- Institute of Stem Cell and Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Republic of Korea.
- Vet-ICT Convergence Education and Research Center (VICERC), Chungbuk National University, Cheongju, Republic of Korea.
- Chungbuk National University Hospital, Cheongju, Republic of Korea.
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13
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Li Y, Ming R, Zhang T, Gao Z, Wang L, Yang Y, Shen K, Wei C, Zhu Y, Li J, Zheng S, Luo Z, Ding Y, Xuan J, Hu Q, Yang Y, Gu J, Wei C. TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis. Cancer Res 2025; 85:84-100. [PMID: 39325960 DOI: 10.1158/0008-5472.can-24-0158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/12/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024]
Abstract
Metabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. In this study, we identified that tectonic family member 1 (TCTN1) promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo and induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor epithelial-mesenchymal transition and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma. Significance: TCTN1 activates fatty acid oxidation to induce melanoma mesenchymal phenotype switching and invasion by promoting the binding of the subunits of MTP, which can be targeted with fluprostenol to inhibit melanoma metastasis.
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Affiliation(s)
- Yinlam Li
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Ren Ming
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Tianyi Zhang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Zixu Gao
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Lu Wang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Yang Yang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Kangjie Shen
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Chenlu Wei
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Yu Zhu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Jianrui Li
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Shaoluan Zheng
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital (Xiamen), Fudan University, Shanghai, P. R. China
| | - Zucheng Luo
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Yiteng Ding
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Jiangying Xuan
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Qianrong Hu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Yanwen Yang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Jianying Gu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Chuanyuan Wei
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
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14
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Liu J, Lu J, Wu L, Zhang T, Wu J, Li L, Tai Z, Chen Z, Zhu Q. Targeting tumor-associated macrophages: Novel insights into immunotherapy of skin cancer. J Adv Res 2025; 67:231-252. [PMID: 38242529 PMCID: PMC11725115 DOI: 10.1016/j.jare.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/19/2023] [Accepted: 01/11/2024] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND The incidence of skin cancer is currently increasing, and conventional treatment options inadequately address the demands of disease management. Fortunately, the recent rapid advancement of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era for numerous cancer patients. However, the efficacy of immunotherapy remains suboptimal due to the impact of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a major component of the TME, play crucial roles in tumor invasion, metastasis, angiogenesis, and immune evasion, significantly impacting tumor development. Consequently, TAMs have gained considerable attention in recent years, and their roles have been extensively studied in various tumors. However, the specific roles of TAMs and their regulatory mechanisms in skin cancer remain unclear. AIM OF REVIEW This paper aims to elucidate the origin and classification of TAMs, investigate the interactions between TAMs and various immune cells, comprehensively understand the precise mechanisms by which TAMs contribute to the pathogenesis of different types of skin cancer, and finally discuss current strategies for targeting TAMs in the treatment of skin cancer. KEY SCIENTIFIC CONCEPTS OF OVERVIEW With a specific emphasis on the interrelationship between TAMs and skin cancer, this paper posits that therapeutic modalities centered on TAMs hold promise in augmenting and harmonizing with prevailing clinical interventions for skin cancer, thereby charting a novel trajectory for advancing the landscape of immunotherapeutic approaches for skin cancer.
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Affiliation(s)
- Jun Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China
| | - Jiaye Lu
- School of Medicine, Shanghai University, 99 Shangda Road, Shanghai 200444, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China
| | - Ling Wu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China
| | - Tingrui Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China
| | - Junchao Wu
- School of Medicine, Shanghai University, 99 Shangda Road, Shanghai 200444, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China
| | - Lisha Li
- School of Medicine, Shanghai University, 99 Shangda Road, Shanghai 200444, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China
| | - Zongguang Tai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China.
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China.
| | - Quangang Zhu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, China; Shanghai Engineering Research Center of Topical Chinese Medicine, 1278 Baode Road, Shanghai 200443, China.
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15
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Hasan AU, Serada S, Sato S, Obara M, Hirata S, Nagase Y, Kondo Y, Taira E. KDM4B Histone Demethylase Inhibition Attenuates Tumorigenicity of Malignant Melanoma Cells by Overriding the p53-Mediated Tumor Suppressor Pathway. J Cell Biochem 2025; 126:e30643. [PMID: 39358852 DOI: 10.1002/jcb.30643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/01/2024] [Accepted: 08/09/2024] [Indexed: 10/04/2024]
Abstract
Despite significant advances in the treatment of cutaneous melanoma (hereafter melanoma), the prognosis remains less favorable due to therapeutic resistance, which is presumably linked to epigenetic dysregulation. We hypothesized that the histone lysine demethylase KDM4B could play a pivotal role in controlling therapy-resistant melanoma. To validate our hypothesis, we retrieved RNA sequencing data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) program and observed upregulation of KDM4B in both primary and metastatic melanoma, which was associated with poor survival. To explore its role, we used murine B16, human SK-MEL-5, and G-361 melanoma cells as in vitro models of melanoma. We found that KDM4B inhibition using NCGC00244536 increased global levels of H3K9me3 and downregulated the expressions of cell cycle progression-related genes Cdk1, Cdk4, Ccnb1, and Ccnd1. Moreover, genetic ablation of KDM4B or its chemical inhibition using NCGC00244536 reduced p53 production by upregulating MDM2, which enhances the proteolytic degradation of p53. Interestingly, despite the reduction of p53, these interventions augmented apoptosis and senescence-induced cell death by activating pathways downstream of p53, as evidenced by reduced levels of pro-survival Bcl-2 and Bcl-xL proteins and increased production of pro-apoptotic cleaved caspase-3, caspase-7, Bax, and the senescence inducer Cdkn1a. Compared to the FDA-approved anti-melanoma agent dacarbazine, NCGC00244536 exhibited more pronounced cytotoxic and antiproliferative effects in melanoma cells. Importantly, NCGC00244536 demonstrated minimal cytotoxicity to low Kdm4b-expressing mouse embryonic fibroblasts. In conclusion, our findings suggest that KDM4B inhibition can override the antitumor effect of p53, and potentially serve as a therapeutic strategy for melanoma.
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Affiliation(s)
- Arif Ul Hasan
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Satoshi Serada
- Department of Molecular Pathophysiology, Institute for Biomedical Sciences, Iwate Medical University, Iwate, Japan
| | - Sachiko Sato
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Mami Obara
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Sho Hirata
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Yukako Nagase
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Yukiko Kondo
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Eiichi Taira
- Department of Pharmacology, School of Medicine, Iwate Medical University, Iwate, Japan
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16
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Gaudel C, Pisibon C, Soysouvanh F, Giuliano S, Picard-Gauci A, Leclerc J, Hofman P, Bahadoran P, Bertolotto C, Ballotti R. Loss of LYN Is Frequent in Targeted Therapy-Resistant Melanoma Cells and Favors Metastatic Properties. J Invest Dermatol 2025; 145:214-218.e5. [PMID: 39033988 DOI: 10.1016/j.jid.2024.06.1286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/23/2024] [Accepted: 06/01/2024] [Indexed: 07/23/2024]
Affiliation(s)
- Céline Gaudel
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France
| | - Céline Pisibon
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France; Equipe labellisée ARC 2022, Nice, France
| | - Frédéric Soysouvanh
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France
| | - Serena Giuliano
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France; Equipe labellisée ARC 2022, Nice, France
| | - Alexandra Picard-Gauci
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France; Département de Dermatologie, CHU de Nice, Nice, France
| | - Justine Leclerc
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France
| | - Paul Hofman
- Université Côte d'Azur, Nice, France; Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, FHU OncoAge, IHU RespirERA, Nice, France
| | - Philippe Bahadoran
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France; Equipe labellisée ARC 2022, Nice, France; Département de Dermatologie, CHU de Nice, Nice, France
| | - Corine Bertolotto
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France; Equipe labellisée Ligue Contre le Cancer 2020, Nice, France
| | - Robert Ballotti
- Université Côte d'Azur, Nice, France; Inserm U1065, Biology and Pathologies of Mélanocytes, Team 1, Centre Méditerranéen de Médecine Moléculaire, Nice, France; Equipe labellisée ARC 2022, Nice, France.
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17
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Zhang D, Zhang M, Fan H, Sun R, Liu J, Ma W. FA-PEG Modified ZIF(Mn) Nanoparticles Loaded with Baicalin for Imaging-Guided Treatment of Melanoma in Mice. Int J Nanomedicine 2024; 19:13593-13613. [PMID: 39723175 PMCID: PMC11669047 DOI: 10.2147/ijn.s493185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/07/2024] [Indexed: 12/28/2024] Open
Abstract
Background Melanoma is an aggressive skin tumor with limited therapeutic options due to rapid proliferation, early metastasis, and poor prognosis. Baicalin (BA), a natural flavonoid, shows promise in inducing ferroptosis and apoptosis but faces challenges of poor solubility and bioavailability. To address these issues, we developed a multifunctional drug delivery system: manganese-doped ZIF-8 nanoparticles (ZIF(Mn)) loaded with BA and modified with folic acid (FA) and polyethylene glycol (PEG). FA targets melanoma cells by exploiting folate receptor overexpression, while PEG enhances biocompatibility and systemic circulation. Manganese enables magnetic resonance (MR) imaging for real-time, non-invasive therapy monitoring. Methods BA-loaded ZIF(Mn)/FA-PEG nanoparticles were synthesized via a one-pot method, enabling drug encapsulation, Mn²+ incorporation, and surface modification. The nanoparticles were comprehensively characterized (particle size, Zeta potential, FTIR, and XRD). Cytotoxicity and cellular uptake were evaluated in B16-F10 melanoma cells, and in vivo experiments in C57BL/6J mice investigated MR imaging capability, antitumor efficacy, and biosafety. Results BA@ZIF(Mn)/FA-PEG nanoparticles demonstrated excellent stability, a BA loading capacity of 33.50 ± 0.04%, and pH-responsive release, with accelerated drug release under acidic tumor conditions. Mn²+ provided strong T1-weighted MR imaging contrast. Cellular and animal studies showed enhanced uptake, reduced premature drug release, and improved compatibility. Mechanistically, the nanoparticles induced significant ferroptosis and apoptosis in melanoma cells, leading to potent antitumor effects. Conclusion The BA@ZIF(Mn)/FA-PEG nanoplatform effectively integrates targeted delivery, imaging guidance, and dual ferroptosis-apoptosis induction, offering a promising strategy for improving melanoma treatment outcomes.
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Affiliation(s)
- Dong Zhang
- Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of China
| | - Mogen Zhang
- Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of China
| | - Huiping Fan
- Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of China
| | - Rui Sun
- Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of China
| | - Jiayun Liu
- Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of China
| | - Weiyuan Ma
- Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of China
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18
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Koshrovski-Michael S, Ajamil DR, Dey P, Kleiner R, Tevet S, Epshtein Y, Green Buzhor M, Khoury R, Pozzi S, Shenbach-Koltin G, Yeini E, Woythe L, Blau R, Scomparin A, Barshack I, Florindo HF, Lazar S, Albertazzi L, Amir RJ, Satchi-Fainaro R. Two-in-one nanoparticle platform induces a strong therapeutic effect of targeted therapies in P-selectin-expressing cancers. SCIENCE ADVANCES 2024; 10:eadr4762. [PMID: 39671487 PMCID: PMC11641104 DOI: 10.1126/sciadv.adr4762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 11/05/2024] [Indexed: 12/15/2024]
Abstract
Combined therapies in cancer treatment aim to enhance antitumor activity. However, delivering multiple small molecules imposes challenges, as different drugs have distinct pharmacokinetic profiles and tumor penetration abilities, affecting their therapeutic efficacy. To circumvent this, poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-based nanoparticles were developed as a platform for the codelivery of synergistic drug ratios, improving therapeutic efficacy by increasing the percentage of injected dose reaching the tumor. Nonetheless, extravasation-dependent tumor accumulation is susceptible to variations in tumor vasculature; therefore, PLGA-PEG was modified with sulfates to actively target P-selectin-expressing cancers. Here, we show the potential of our platform in unique three-dimensional (3D) in vitro and in vivo models. The P-selectin-targeted nanoparticles showed enhanced accumulation in 3D spheroids and tissues of P-selectin-expressing BRAF-mutated melanomas and BRCA-mutated breast cancers, resulting in superior in vivo efficacy and safety. This nanoplatform could advance the codelivery of a plethora of anticancer drug combinations to various P-selectin-expressing tumors.
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Affiliation(s)
- Shani Koshrovski-Michael
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Daniel Rodriguez Ajamil
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Pradip Dey
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Department of Chemistry, Siksha Bhavana, Visva-Bharati University, Santiniketan, West Bengal 731235, India
| | - Ron Kleiner
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Shahar Tevet
- The Center for Physics and Chemistry of Living Systems, Tel Aviv University, Tel Aviv 6997801, Israel
- Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
- Tel Aviv University Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel
- ADAMA Center for Novel Delivery Systems in Crop Protection, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Yana Epshtein
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Marina Green Buzhor
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Rami Khoury
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sabina Pozzi
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Gal Shenbach-Koltin
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Eilam Yeini
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Laura Woythe
- Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology (TU/e), 5612AZ Eindhoven, Netherlands
| | - Rachel Blau
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Anna Scomparin
- Department of Drug Science and Technology, University of Turin, Turin 10125, Italy
| | - Iris Barshack
- Department of Pathology, Sheba Medical Center, Tel Hashomer, Ramat-Gan 52621, Israel
- Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Helena F. Florindo
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-003, Portugal
| | - Shlomi Lazar
- Department of Pharmacology, Israel Institute of Biological Research (IIBR), Ness-Ziona 74100, Israel
| | - Lorenzo Albertazzi
- Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology (TU/e), 5612AZ Eindhoven, Netherlands
| | - Roey J. Amir
- The Center for Physics and Chemistry of Living Systems, Tel Aviv University, Tel Aviv 6997801, Israel
- Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
- Tel Aviv University Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel
- ADAMA Center for Novel Delivery Systems in Crop Protection, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ronit Satchi-Fainaro
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Tel Aviv University Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
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19
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Hasanzadeh S, Farokh P, Vazifeh F, Hosseini GS, Rezaei L, Ghaedrahmati M, Razaghi Z, Rezaei Tavirani M, Robati RM. The efficacy and safety of relatlimab/nivolumab combination therapy in patients with advanced melanoma: a systematic review. Arch Dermatol Res 2024; 317:65. [PMID: 39636334 DOI: 10.1007/s00403-024-03579-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/07/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
Finding a treatment approach with high efficacy and minimal adverse reactions for advanced melanoma is still challenging. This study aimed to review and summarize available evidence regarding the effectiveness of the newly FDA-approved combination therapy of Relatmlimab and Nivolumab in patients with advanced melanoma and its comorbidities. We searched MEDLINE, EMBASE, and Cochrane Library for studies published in any language till 29/11/2023. We used the following Mesh and Emtree words, "melanoma" AND "relatlimab" AND "nivolumab". We screened 398 articles and included two single-arm clinical trials (N = 2) and one randomized clinical trial (RCT) (N = 1). In conclusion, The relatlimab/nivolumab combination therapy showed promising results for advanced melanoma patients. However, further research and longer follow-up periods are needed to compare it with previous treatments and validate its long-term effectiveness and safety.
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Affiliation(s)
- Saba Hasanzadeh
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Farokh
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Vazifeh
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Golsa Sadat Hosseini
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Rezaei
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhgan Ghaedrahmati
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Razaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza M Robati
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Dermatology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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20
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Lengyel AS, Meznerics FA, Galajda NÁ, Gede N, Kói T, Mohammed AA, Péter PN, Lakatos AI, Krebs M, Csupor D, Bánvölgyi A, Hegyi P, Holló P, Kemény LV. Safety and Efficacy Analysis of Targeted and Immune Combination Therapy in Advanced Melanoma-A Systematic Review and Network Meta-Analysis. Int J Mol Sci 2024; 25:12821. [PMID: 39684531 DOI: 10.3390/ijms252312821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/23/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
The combinations of BRAF inhibitor-based targeted therapies with immune checkpoint inhibitors currently represent less common therapeutic approaches in advanced melanoma. The aim of this study was to assess the safety and efficacy of currently available melanoma treatments by conducting a systematic review and network meta-analysis. Four databases were systematically searched for randomized clinical studies that included patients with advanced/metastatic melanoma receiving chemotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitor therapy, or combinations thereof. The primary endpoints were treatment-related adverse events (TRAE), serious adverse events (SAE) of grade ≥ 3 adverse events, therapy discontinuation, progression-free survival (PFS), as well as objective response rate (ORR) and complete response rate (CRR). A total of 63 articles were eligible for our systematic review; 59 of them were included in the statistical analysis. A separate subgroup analysis was conducted to evaluate the efficacy outcomes, specifically in BRAF-positive patients. Triple combination therapy or triple therapy (inhibiting BRAF, MEK and PD1/PDL1 axis) showed significantly longer progression-free survival compared to BRAF + MEK combination therapies (HR = 0.76; 95% CI 0.64-0.9), but similar objective and complete response rates in BRAF-mutated melanoma. This safety analysis suggests that triple therapy is not inferior to combined immune checkpoint inhibitors (ICI) and BRAF/MEK therapies in terms of serious adverse events and therapy discontinuation rates. However, monotherapies and BRAF/MEK combinations showed notable advantage over triple therapy in terms of treatment-related adverse events. Combination strategies including BRAF/MEK-targeted therapies with ICI therapies are effective first-line options for advanced, BRAF-mutant melanoma; however, they are associated with more frequent side effects. Therefore, future RCTs are required to evaluate and identify high-risk subpopulations where triple therapy therapies should be considered.
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Affiliation(s)
- Anna Sára Lengyel
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary
- Department of Physiology, Semmelweis University, Tűzoltó Str. 37-47, 1094 Budapest, Hungary
| | - Fanni Adél Meznerics
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
| | - Noémi Ágnes Galajda
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
| | - Noémi Gede
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, 7623 Pécs, Hungary
| | - Tamás Kói
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- Department of Stochastics, Institute of Mathematics, Budapest University of Technology and Economics, 1111 Budapest, Hungary
| | - Alzahra Ahmed Mohammed
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary
| | - Petra Nikolett Péter
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary
- Department of Physiology, Semmelweis University, Tűzoltó Str. 37-47, 1094 Budapest, Hungary
| | - Alexandra It Lakatos
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary
- Department of Physiology, Semmelweis University, Tűzoltó Str. 37-47, 1094 Budapest, Hungary
| | - Máté Krebs
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary
- Department of Physiology, Semmelweis University, Tűzoltó Str. 37-47, 1094 Budapest, Hungary
| | - Dezső Csupor
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, 7623 Pécs, Hungary
- Institute of Clinical Pharmacy, Faculty of Pharmacy, University of Szeged, 6725 Szeged, Hungary
| | - András Bánvölgyi
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, 7623 Pécs, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, 1083 Budapest, Hungary
| | - Péter Holló
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
| | - Lajos V Kemény
- Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary
- Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary
- Department of Physiology, Semmelweis University, Tűzoltó Str. 37-47, 1094 Budapest, Hungary
- MTA-SE Lendület "Momentum" Dermatooncology Research Group, 1094 Budapest, Hungary
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21
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Hani U, Choudhary VT, Ghazwani M, Alghazwani Y, Osmani RAM, Kulkarni GS, Shivakumar HG, Wani SUD, Paranthaman S. Nanocarriers for Delivery of Anticancer Drugs: Current Developments, Challenges, and Perspectives. Pharmaceutics 2024; 16:1527. [PMID: 39771506 PMCID: PMC11679327 DOI: 10.3390/pharmaceutics16121527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/06/2024] [Accepted: 11/16/2024] [Indexed: 01/11/2025] Open
Abstract
Cancer, the most common condition worldwide, ranks second in terms of the number of human deaths, surpassing cardiovascular diseases. Uncontrolled cell multiplication and resistance to cell death are the traditional features of cancer. The myriad of treatment options include surgery, chemotherapy, radiotherapy, and immunotherapy to treat this disease. Conventional chemotherapy drug delivery suffers from issues such as the risk of damage to benign cells, which can cause toxicity, and a few tumor cells withstand apoptosis, thereby increasing the likelihood of developing tolerance. The side effects of cancer chemotherapy are often more pronounced than its benefits. Regarding drugs used in cancer chemotherapy, their bioavailability and stability in the tumor microenvironment are the most important issues that need immediate addressing. Hence, an effective and reliable drug delivery system through which both rapid and precise targeting of treatment can be achieved is urgently needed. In this work, we discuss the development of various nanobased carriers in the advancement of cancer therapy-their properties, the potential of polymers for drug delivery, and recent advances in formulations. Additionally, we discuss the use of tumor metabolism-rewriting nanomedicines in strengthening antitumor immune responses and mRNA-based nanotherapeutics in inhibiting tumor progression. We also examine several issues, such as nanotoxicological studies, including their distribution, pharmacokinetics, and toxicology. Although significant attention is being given to nanotechnology, equal attention is needed in laboratories that produce nanomedicines so that they can record themselves in clinical trials. Furthermore, these medicines in clinical trials display overwhelming results with reduced side effects, as well as their ability to modify the dose of the drug.
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Affiliation(s)
- Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia; (U.H.); (M.G.)
| | - Vikram T. Choudhary
- Department of Pharmaceutics, The Oxford College of Pharmacy, Hongsandra, Bengaluru 560068, India;
| | - Mohammed Ghazwani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia; (U.H.); (M.G.)
| | - Yahia Alghazwani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia;
| | - Riyaz Ali M. Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSS AHER), Mysuru 570015, India; (R.A.M.O.); (H.G.S.)
| | - Gururaj S. Kulkarni
- Department of Pharmaceutics, The Oxford College of Pharmacy, Hongsandra, Bengaluru 560068, India;
| | - Hosakote G. Shivakumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSS AHER), Mysuru 570015, India; (R.A.M.O.); (H.G.S.)
| | - Shahid Ud Din Wani
- Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Srinagar 190006, India;
| | - Sathishbabu Paranthaman
- Department of Cell Biology and Molecular Genetics, Sri Devraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Kolar 563103, India;
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Huang J, Wang X, Li Z. Dissolving microneedles: standing out in melanoma treatment. J Mater Chem B 2024; 12:11573-11595. [PMID: 39431729 DOI: 10.1039/d4tb01142b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
Melanoma is one of the most significant and dangerous superficial skin tumors with a high fatality rate, thanks to its high invasion rate, drug resistance and frequent metastasis properties. Unfortunately, researchers for decades have demonstrated that the outcome of using conventional therapies like chemotherapy and immunotherapy with normal drug delivery routes, such as an oral route to treat melanoma was not satisfactory. The severe adverse effects, slow drug delivery efficiency and low drug accumulation at targeted malignancy sites all lead to poor anti-cancer efficacy and terrible treatment experience. As a novel transdermal drug delivery system, microneedles (MNs) have emerged as an effective solution to help improve the low cure rate of melanoma. The excellent characteristics of MNs make it easy to penetrate the stratum corneum (SC) and then locally deliver the drug towards the lesion without drug leakage to mitigate the occurrence of side effects and increase the drug accumulation. Therefore, loading chemotherapeutic drugs or immunotherapy drugs in MNs can address the problems mentioned above, and MNs play a crucial role in improving the curative effect of conventional treatment methods. Notably, novel tumor therapies like photothermal therapy (PTT), photodynamic therapy (PDT) and chemodynamic therapy (CDT) have shown good application prospects in the treatment of melanoma, and MNs provide a valid platform for the combination of conventional therapies and novel therapies by encompassing different therapeutic materials in the matrix of MNs. The synergistic effect of multiple therapies can enhance the therapeutic efficacy compared to single therapies, showing great potential in melanoma treatment. Dissolving MNs have been the most commonly used microneedles in the treatment of melanoma in recent years, mainly because of their simple fabrication procedure and enough drug loading. So, considering the increasing use of dissolving MNs, this review collects research studies published in the last four years (2020-2024) that have rarely been included in other reviews to update the progress of applications of dissolving MNs in anti-melanoma treatment, especially in synergistic therapies. This review also presents current design and fabrication methods of dissolving MNs; the limitations of microneedle technology in the treatment of melanoma are comprehensively discussed. This review can provide valuable guidance for their future development.
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Affiliation(s)
- Jingting Huang
- Department of Burn and Plastic Surgery, Sichuan University West China Hospital, Chengdu, China.
| | - Xihao Wang
- Department of Burn and Plastic Surgery, Sichuan University West China Hospital, Chengdu, China.
| | - Zhengyong Li
- Department of Burn and Plastic Surgery, Sichuan University West China Hospital, Chengdu, China.
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23
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Wu Z, Wang Z, Hua Z, Ji Y, Ye Q, Zhang H, Yan W. Prognostic signature and immunotherapeutic relevance of Focal adhesion signaling pathway-related genes in osteosarcoma. Heliyon 2024; 10:e38523. [PMID: 39524888 PMCID: PMC11550747 DOI: 10.1016/j.heliyon.2024.e38523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 09/22/2024] [Accepted: 09/25/2024] [Indexed: 11/16/2024] Open
Abstract
Background As the most common primary malignant bone tumor in children and adolescents, osteosarcoma currently lacks an effective clinical cure. Focal adhesion plays a crucial role in tumor invasion, migration, and drug resistance by mediating communication between the extracellular matrix and tumor cells. This study investigated the prognostic features and immunotherapeutic relevance of focal adhesion pathway-related genes in osteosarcoma to aid in the development of new therapeutic options. Methods We obtained mutational, transcriptomic, gene expression, and clinical data of osteosarcoma patients from the Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective (TARGET) databases. Differentially expressed genes were screened, followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Kaplan-Meier survival analysis was performed for genes related to the focal adhesion pathway, and multivariate Cox regression analysis was employed to construct a prognostic signature model. Genes such as SIGLEC15, TIGIT, CD274, HAVCR2, PDCD1, CTLA4, and LAG3 were extracted from the TARGET and CCLE databases for osteosarcoma patients and osteosarcoma cell lines, respectively,to observe the expression of immune checkpoint-related genes. Finally, qRT-PCR was used to verify the expression of these immune checkpoint-related genes in osteosarcoma cell lines. Results In our study, 376 samples were analyzed, including 369 osteosarcoma samples and 7 normal tissue samples. We identified 50 up-regulated and 28 down-regulated differentially expressed genes. Among these, 10 Candidate genes relative to focal Adhesion were selected, and CAV1, ZYX, and ITGA5 were found to have a significant prognostic role based on survival analysis of osteosarcoma samples from the TARGET database. A predictive signature model related to the focal adhesion signaling pathway was constructed using these genes, and the AUCs of the 1-year, 3-year, and 5-year ROC curves were 0. 647, 0. 712, and 0. 717, respectively. The overall survival (OS) rate of osteosarcoma patients with high-risk scores was poorer than those with low-risk scores. Then, samples were divided into two subgroups based on the expression of the three genes, revealing significant differences in the expression of certain immune checkpoint-related genes between the subgroups. Additionally, above three genes and immune checkpoint-related genes in osteosarcoma cell lines were extracted from the CCLE database, showing high expression levels in eight osteosarcoma cell lines. We observed that CD274 and PDCD1LG2 were highly expressed in some osteosarcoma cell lines. Finally, the expression of CAV1, ZYX, ITGA5, CD80, CD274, and PDCD1LG2 in osteosarcoma cell lines was verified by qRT-PCR. Conclusions Our study validated the prognostic role of three focal adhesion pathway-related genes (ZYX, CAV1, and ITGA5) in patients with osteosarcoma and constructed a prognostic signature model associated with the focal adhesion signaling pathway. We identified significant differences in the expression of multiple immune checkpoint-related genes among subgroups defined by the three genes. Additionally, CD274 and PDCD1LG2 showed higher expression in osteosarcoma cell lines characterized by these genes. These findings may aid in the selection of effective immunotherapy for specific osteosarcoma patients.
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Affiliation(s)
- Zhiqiang Wu
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhiqing Wang
- Zhabei Central Hospital, No. 619, Zhonghuaxin Road, Jing'an District, Shanghai, 200070, China
| | - Zhanqiang Hua
- Department of Orthopedics, Shanghai Electric Power Hospital, Shanghai, 200050, China
| | - Yingzheng Ji
- Department of Orthopedics, Naval Medical Center of PLA, Second Military Medical University, China
| | - Qingrong Ye
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Hao Zhang
- Department of Orthopedics, Naval Medical Center of PLA, Second Military Medical University, China
| | - Wangjun Yan
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
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24
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Macandog ADG, Catozzi C, Capone M, Nabinejad A, Nanaware PP, Liu S, Vinjamuri S, Stunnenberg JA, Galiè S, Jodice MG, Montani F, Armanini F, Cassano E, Madonna G, Mallardo D, Mazzi B, Pece S, Tagliamonte M, Vanella V, Barberis M, Ferrucci PF, Blank CU, Bouvier M, Andrews MC, Xu X, Santambrogio L, Segata N, Buonaguro L, Cocorocchio E, Ascierto PA, Manzo T, Nezi L. Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients. Cell Host Microbe 2024; 32:2004-2018.e9. [PMID: 39481388 PMCID: PMC11629153 DOI: 10.1016/j.chom.2024.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 09/15/2024] [Accepted: 10/07/2024] [Indexed: 11/02/2024]
Abstract
Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.
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Affiliation(s)
- Angeli D G Macandog
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Carlotta Catozzi
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Mariaelena Capone
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | - Amir Nabinejad
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Padma P Nanaware
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Shujing Liu
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4238, USA
| | - Smita Vinjamuri
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612-7342, USA
| | - Johanna A Stunnenberg
- Netherlands Cancer Institute (NKI)-AVL, North Holland, Amsterdam 1066 CX, the Netherlands
| | - Serena Galiè
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Maria Giovanna Jodice
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Francesca Montani
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Federica Armanini
- Department of CIBIO, University of Trento, Trento, Povo 38123, Italy
| | - Ester Cassano
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Gabriele Madonna
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | - Domenico Mallardo
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | | | - Salvatore Pece
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Maria Tagliamonte
- Innovative Immunological Models, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | - Vito Vanella
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | - Massimo Barberis
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | | | - Christian U Blank
- Netherlands Cancer Institute (NKI)-AVL, North Holland, Amsterdam 1066 CX, the Netherlands
| | - Marlene Bouvier
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612-7342, USA
| | - Miles C Andrews
- Department of Medicine, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4238, USA
| | - Laura Santambrogio
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Nicola Segata
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy; Department of CIBIO, University of Trento, Trento, Povo 38123, Italy
| | - Luigi Buonaguro
- Innovative Immunological Models, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | - Emilia Cocorocchio
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy
| | - Paolo A Ascierto
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples 80131, Italy
| | - Teresa Manzo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy
| | - Luigi Nezi
- Department of Experimental Oncology, Istituto Europeo di Oncologia-IRCCS, Milan 20139, Italy.
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25
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Cai X, Lin J, Li C, Xu T, Chen C, Lan B, Wang X, Bai S, Huang Y, Zhang H, Si L, Chen Y. MET amplification correlates with poor prognosis and immunotherapy response as a subtype of melanoma: a multicenter retrospective study. BMC Cancer 2024; 24:1384. [PMID: 39528978 PMCID: PMC11555915 DOI: 10.1186/s12885-024-13163-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Mesenchymal epithelial transition factor (MET) variant is an independent prognostic factor for worse prognosis in patients with lung cancer or gastroesophageal adenocarcinoma. MET gene variants can be regarded as a subtype of melanoma but there is a lack of studies regarding the frequency of MET genetic alterations and the efficacy of immunotherapy in melanoma patients. The purpose of this study is to explore potential therapeutic strategies for melanoma subtypes with MET alterations. METHODS A total of 1751 malignant melanomas were analyzed to illustrate the landscape of MET mutations. We collected 55 melanoma cases from multicenter for a retrospective cohort from 2010 to 2023. We analyzed the impact of MET amplification on the efficacy of immunotherapy in the retrospective cohort after propensity score matching (PSM) and a pancancer cohort. CIBERSORT was used to evaluate the immune infiltration. RESULTS There were no instances of MET 14 exon skipping, and only instances of MET amplification were found in the 1751 melanomas and our retrospective cohort. Cox proportional hazards model analysis showed that MET amplification (P = 0.006) was significantly associated with poorer overall survival (OS) in patients who received immunotherapy as the first-line treatment. Compared with patients with MET amplification, patients in the negative control (NC) group had a significantly better OS (P = 0.022) after PSM. Analysis of 1661 pancancer cases with the MSK-IMPACT assay showed that patients receiving immunotherapy in the MET amplification group had a trend toward worse OS than those without MET amplification (P = 0.025). CONCLUSIONS This database analysis showed that the main type of MET mutation is amplification in malignant melanoma. MET-amplified solid tumors might be considered for targeted therapy, as MET amplification can be regarded as a risk factor affecting the prognosis of patients with tumors treated with immunotherapy.
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Affiliation(s)
- Xiaojun Cai
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jing Lin
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Cancer Bio-Immunotherapy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Caili Li
- Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ting Xu
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Chuanben Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Bin Lan
- Laboratory of Radiation Oncology and Radiobiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Xuefeng Wang
- Innovation Center for Cancer Research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Shengjie Bai
- Beijing GenePlus Technology Co., Ltd, Beijing, China
| | - Yufang Huang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Huishan Zhang
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Lu Si
- Innovation Center for Cancer Research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yu Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
- Cancer Bio-Immunotherapy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
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26
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Wang Y, Su H, Wang X, Tu C, Xiao T, Ren B, Wang S. FOXN3 Regulates Autophagic Activity to Suppress Drug Resistance in Melanoma Cells. Clin Cosmet Investig Dermatol 2024; 17:2505-2518. [PMID: 39530064 PMCID: PMC11552389 DOI: 10.2147/ccid.s462854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/22/2024] [Indexed: 11/16/2024]
Abstract
Background The forkhead box (FOX) family member FOXN3 has been reported to inhibit transcriptional activity associated with regulating tumor development. However, the role of FOXN3 in the pathogenesis of melanoma is not well understood. Objective To investigate the biological functions of FOXN3 in drug resistance of melanoma. Materials and Methods The expression of FOXN3 in melanoma was investigated using Gene Expression profiling interactive analysis (GEPIA) and Linkedomics databases. Melanoma cell proliferation, invasion, and migration were assessed using the colony formation assay, the scratch wound healing test, the Transwell invasion assay, and the nude mice xenograft to determine the effects of FOXN3 over-expression and depletion. The functional role of the transcriptional regulator in melanoma cells was tested through chromatin immunoprecipitation, immunofluorescence. Results FOXN3 was downregulated in melanoma. Over-expression of FOXN3 inhibited the proliferation and motility of melanoma cells, whereas FOXN3 knockdown significantly enhanced the proliferation and motility of melanoma cells. Overexpression of FOXN3 reduced autophagic activity in melanoma cells. Enhanced autophagic activity in drug-resistant melanoma cell lines is related to drug-sensitive cells, and significant differences in FOXN3 localization were observed when comparing melanoma cells that were sensitive and resistant to Vemurafenib. Additionally, FOXN3 has been identified as binding to the promoter region of the cancer antigen Fibrous Sheath Interacting Protein 1 (FSIP1), thereby regulating the expression of this gene. Conclusion FOXN3 functions as an important regulator of the development and progression of Vemurafenib-resistant melanoma cells, partly owing to its binding to the FISP1. As such, FOXN3 may represent a relevant target for therapeutic interventions in patients suffering from drug-resistant melanoma.
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Affiliation(s)
- Yaqi Wang
- Department of Dermatology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Hui Su
- Department of Dermatology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
| | - Xiaopeng Wang
- Department of Dermatology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
| | - Chen Tu
- Department of Dermatology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
| | - Tong Xiao
- Department of Dermatology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
| | - Bincheng Ren
- Department of Rheumatology and Immunology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
| | - Shuang Wang
- Department of Dermatology, Xi’an Jiaotong University The Second Affiliated Hospital, Xi’an, Shaanxi, People’s Republic of China
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27
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Zhou B, Sha S, Wang Q, Sun S, Tao J, Zhu J, Dong L. The prognostic implications of cuproptosis-related gene signature and the potential of PPIC as a promising biomarker in cutaneous melanoma. Pigment Cell Melanoma Res 2024; 37:864-880. [PMID: 39115044 DOI: 10.1111/pcmr.13185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/28/2024] [Accepted: 06/23/2024] [Indexed: 10/29/2024]
Abstract
Cutaneous melanoma is the most lethal of all skin tumors. Recently, cuproptosis, a novel form of cell death linked to oxidative phosphorylation, has emerged as an important factor. However, the precise role of cuproptosis in melanoma remains unclear. Our research explored the potential links between cuproptosis-related genes, prognosis, immune microenvironments, and melanoma treatments. Significantly, cuproptosis regulators showed remarkable differences between melanoma and normal tissues, establishing their relevance to melanoma. The newly developed cuproptosis-related gene signature (CGS) demonstrated a robust ability to predict overall survival (OS) in melanoma. We constructed a novel nomogram that combined clinical features with CGS to improve predictive accuracy. In addition, the study revealed correlations between CGS and immune cell populations, including CD8+T cells, Tfh cells, B cells, and myeloid-derived suppressor cells. Within the CGS, Peptidylprolyl isomerase C (PPIC) emerged as the most strongly associated with poor prognosis and drug resistance in melanoma. PPIC was identified as a promoter of melanoma progression, enhancing cell invasiveness while concurrently suppressing CD8+T cell activation. This comprehensive study not only elucidated the intricate connections between CGS, melanoma prognosis, immune microenvironment, and drug resistance but also provided compelling evidence supporting PPIC as a promising biomarker for predicting OS in melanoma treatment.
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Affiliation(s)
- Bin Zhou
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
| | - Shanshan Sha
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
| | - Qi Wang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
| | - Shuomin Sun
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
| | - Juan Tao
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
| | - Jinjin Zhu
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
| | - Liyun Dong
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
- Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, China
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28
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Ning N, Tian Z, Feng H, Feng X. Lnc NEAT1 facilitates the progression of melanoma by targeting the miR-152-3p/CDK6 axis: An observational study. Medicine (Baltimore) 2024; 103:e40379. [PMID: 39495991 PMCID: PMC11537649 DOI: 10.1097/md.0000000000040379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 10/16/2024] [Indexed: 11/06/2024] Open
Abstract
Long noncoding (Lnc) RNAs are novel regulators in melanoma. Lnc nuclear enriched autosomal transcript 1 (NEAT1) was reportedly upregulated in melanoma; however, the functional roles and mechanisms of Lnc NEAT1 need further investigation. Therefore, we used quantitative real-time PCR to determine the mRNA levels of Lnc NEAT1, miR-152-3p, and cyclin-dependent protein kinase 6 (CDK6). The protein level of CDK6 was determined by Western blot. Cell counting kit 8 and colony formation assays were used to assess cell proliferation. Cell migration was measured by wound healing and Transwell assays. Direct binding of the indicated molecules was verified by an RNA-binding protein immunoprecipitation assay and a dual luciferase reporter assay. The results revealed that Lnc NEAT1 and CDK6 were elevated, while miR-152-3p was downregulated in melanoma. Furthermore, Lnc NEAT1 was positively correlated with CDK6 expression and negatively correlated with miR-152-3p level. Furthermore, Lnc NEAT1 facilitated proliferation, migration, and invasion of melanoma cells. The underlying mechanism is that Lnc NEAT1 serves as a sponge for miR-152-3p to suppress the inhibitory effect of miR-152-3p on CDK6. Furthermore, the miR-152-3p/ CDK6 axis was implicated in the progression of melanoma accelerated by Lnc NEAT1. Taken together, Lnc NEAT1 may promote melanoma development by serving as an endogenous sponge of miR-152-3p, increasing CDK6 expression, and identifying a new target for the treatment of melanoma.
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Affiliation(s)
- Ning Ning
- Department of Medical Equipment, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Hunan, China
| | - Zeyu Tian
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Hunan, China
| | - Hao Feng
- Department of Dermatology, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Hunan, China
| | - Xing Feng
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, China
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29
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Khan M, Dong Y, Ullah R, Li M, Huang Q, Hu Y, Yang L, Luo Z. Recent Advances in Bacterium-Based Therapeutic Modalities for Melanoma Treatment. Adv Healthc Mater 2024; 13:e2401076. [PMID: 39375965 DOI: 10.1002/adhm.202401076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/16/2024] [Indexed: 10/09/2024]
Abstract
Melanoma is one of the most severe skin cancer indications with rapid progression and a high risk of metastasis. However, despite the accumulated advances in melanoma treatment including adjuvant radiation, chemotherapy, and immunotherapy, the overall melanoma treatment efficacy in the clinics is still not satisfactory. Interestingly, bacterial therapeutics have demonstrated unique properties for tumor-related therapeutic applications, such as tumor-targeted motility, tailorable cytotoxicity, and immunomodulatory capacity of the tumor microenvironment, which have emerged as a promising platform for melanoma therapy. Indeed, the recent advances in genetic engineering and nanotechnologies have boosted the application potential of bacterium-based therapeutics for treating melanoma by further enhancing their tumor-homing, cell-killing, drug delivery, and immunostimulatory capacities. This review provides a comprehensive summary of the state-of-the-art bacterium-based anti-melanoma modalities, which are categorized according to their unique functional merits, including tumor-specific cytotoxins, tumor-targeted drug delivery platforms, and immune-stimulatory agents. Furthermore, a perspective is provided discussing the potential challenges and breakthroughs in this area. The insights in this review may facilitate the development of more advanced bacterium-based therapeutic modalities for improved melanoma treatment efficacy.
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Affiliation(s)
- Mubassir Khan
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Yilong Dong
- Ruian People's Hospital, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325016, P. R. China
| | - Razi Ullah
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Lab for Vascular Implants College of Bioengineering Chongqing University, Chongqing, 400030, P. R. China
| | - Menghuan Li
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| | - Qiping Huang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Yan Hu
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Li Yang
- Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing, Chongqing, 400044, P. R. China
| | - Zhong Luo
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
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30
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Jarab AS, Al-Qerem WA, Khdour LM, Mimi YA, Khdour MR. New emerging treatment options for metastatic melanoma: a systematic review and meta-analysis of skin cancer therapies. Arch Dermatol Res 2024; 316:735. [PMID: 39485529 DOI: 10.1007/s00403-024-03467-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 10/04/2024] [Accepted: 10/16/2024] [Indexed: 11/03/2024]
Abstract
Skin cancer, notably melanoma, poses a significant global health burden, with rising incidence and mortality rates. While therapeutic advancements have improved outcomes, metastatic melanoma remains challenging to treat. This study aims to systematically review systemic treatment options for advanced melanoma, focusing on efficacy and safety in the first-line setting. Through a comprehensive search and meta-analysis of randomized controlled trials conducted from 2013 to 2023, 11 studies encompassing 2816 participants were analyzed. Treatment options included BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib, cobimetinib), and immune checkpoint inhibitors (ipilimumab). Combined therapy with vemurafenib, cobimetinib, and ipilimumab demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to monotherapy, with a significant odds ratio (OR) of 6.95 (95% CI: 4.25-9.64, p < 0.00001) for OS and 2.49 (95% CI: 1.42-3.56, p < 0.00001) for PFS. Additionally, dabrafenib and trametinib combination therapy showed improved outcomes with favorable tolerability, including a significant reduction in adverse event (AE) risk, with an OR of 2.20 (95% CI: 1.72-2.81). Furthermore, our analysis highlighted vemurafenib-associated dermatological toxicities, emphasizing the need for effective management strategies. The study underscores the evolving treatment landscape in melanoma management, with a potential shift towards immune checkpoint inhibitors in the adjuvant setting, particularly for BRAF-mutated disease. However, limitations in meta-analysis methodologies and the need for long-term investigations into treatment implications on survival and quality of life underscore the importance of continued research.
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Affiliation(s)
- Anan S Jarab
- College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
| | - Walid A Al-Qerem
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, 11733, Jordan
| | - Lina M Khdour
- Faculty of Medicine, Al-Quds University, Abu Deis, P.O. Box 20002, West Bank, Palestine
| | - Yousef A Mimi
- Department of Health Sciences, Faculty of Graduated Studies, Arab American University, Jenin, Palestine
| | - Maher R Khdour
- Faculty of Pharmacy, Al-Quds University, Abu Deis, P.O. Box 20002, Jerusalem, Palestine.
- Faculty of Pharmacy, Al-Quds University, Abu Deis, P.O. Box 20002, Jerusalem, Palestine.
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31
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Cheishvili D, Wong C, Karim MM, Golam Kibria M, Jahan N, Chandra Das P, Khair Yousuf A, Islam A, Chandra Das D, Noor-E-Alam SM, Alam S, Rahman M, Khan WA, Al-Mahtab M, Szyf M. Clinical validation of peripheral blood mononuclear cell DNA methylation markers for accurate early detection of hepatocellular carcinoma in Asian patients. COMMUNICATIONS MEDICINE 2024; 4:220. [PMID: 39472687 PMCID: PMC11522327 DOI: 10.1038/s43856-024-00652-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths globally, poses significant challenges in early detection. Improved diagnostic accuracy can drastically influence patient outcomes, emphasizing the need for innovative, non-invasive biomarkers. METHODS This study utilized a cohort of 402 participants, including healthy controls, chronic hepatitis patients, and HCC patients from Bangladesh, to evaluate DNA methylation signatures in peripheral blood mononuclear cells (PBMC). We performed targeted next-generation sequencing on selected genes previously identified to assess their methylation dynamics. The development of M8 and M4 scores was based on these dynamics, using Receiver Operating Characteristic (ROC) analysis to determine their effectiveness in detecting early-stage HCC alongside existing markers such as epiLiver and alpha-fetoprotein (AFP). RESULTS Integration of M8 and M4 scores with epiLiver and AFP significantly enhances diagnostic sensitivity for early-stage HCC. The M4+epiLiver score achieves a sensitivity of 79.4% in Stage A HCC, while combining M4 with AFP increases sensitivity to 88.2-95.7% across all stages, indicating a superior diagnostic performance compared to each marker used alone. CONCLUSIONS Our study confirms that combining gene methylation profiles with established diagnostic markers substantially improves the sensitivity of detecting early-stage HCC. This integrated diagnostic approach holds promise for advancing non-invasive cancer diagnostics, potentially leading to earlier treatment interventions and improved survival rates for high-risk patients.
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Affiliation(s)
- David Cheishvili
- HKG Epitherapeutics Ltd. Unit 313-315, 3/F Biotech Center 2, 11 Science Park West Avenue, Shatin, Hong Kong, SAR, China
- Gerald Bronfman Department of Oncology, McGill University Montreal, Montreal, Canada
| | - Chifat Wong
- HKG Epitherapeutics Ltd. Unit 313-315, 3/F Biotech Center 2, 11 Science Park West Avenue, Shatin, Hong Kong, SAR, China
| | - Mohammad Mahbubul Karim
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Mohammad Golam Kibria
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Nusrat Jahan
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Pappu Chandra Das
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Abul Khair Yousuf
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Atikul Islam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Dulal Chandra Das
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | | | - Sarwar Alam
- Department of Clinical Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mustafizur Rahman
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Wasif A Khan
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka, Bangladesh
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Moshe Szyf
- HKG Epitherapeutics Ltd. Unit 313-315, 3/F Biotech Center 2, 11 Science Park West Avenue, Shatin, Hong Kong, SAR, China.
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Oli AN, Adejumo SA, Rowaiye AB, Ogidigo JO, Hampton-Marcell J, Ibeanu GC. Tumour Immunotherapy and Applications of Immunological Products: A Review of Literature. J Immunol Res 2024; 2024:8481761. [PMID: 39483536 PMCID: PMC11527548 DOI: 10.1155/2024/8481761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 09/23/2024] [Accepted: 09/28/2024] [Indexed: 11/03/2024] Open
Abstract
Malignant tumors, characterized by uncontrolled cell proliferation, are a leading global health challenge, responsible for over 9.7 million deaths in 2022, with new cases expected to rise to 35 million annually by 2050. Immunotherapy is preferred to other cancer therapies, offering precise targeting of malignant cells while simultaneously strengthening the immune system's complex responses. Advances in this novel field of science have been closely linked to a deeper knowledge of tumor biology, particularly the intricate interplay between tumor cells, the immune system, and the tumor microenvironment (TME), which are central to cancer progression and immune evasion. This review offers a comprehensive analysis of the molecular mechanisms that govern these interactions, emphasizing their critical role in the development of effective immunotherapeutic products. We critically evaluate the current immunotherapy approaches, including cancer vaccines, adoptive T cell therapies, and cytokine-based treatments, highlighting their efficacy and safety. We also explore the latest advancements in combination therapies, which synergistically integrate multiple immunotherapeutic strategies to overcome resistance and enhance therapeutic outcomes. This review offers key insights into the future of cancer immunotherapy with a focus on advancing more effective and personalized treatment strategies.
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Affiliation(s)
- Angus Nnamdi Oli
- Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka 420211, Nigeria
| | - Samson Adedeji Adejumo
- Department of Biological Sciences, University of Illinois, Chicago, 845 West Taylor, Chicago 60607, Illinois, USA
- Department of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmaceutical Sciences, Federal University Oye Ekiti, Oye, Ekiti State, Nigeria
| | - Adekunle Babajide Rowaiye
- National Biotechnology Development Agency, Abuja 900211, Nigeria
- Department of Pharmaceutical Science, North Carolina Central University, Durham 27707, North Carolina, USA
| | | | - Jarrad Hampton-Marcell
- Department of Biological Sciences, University of Illinois, Chicago, 845 West Taylor, Chicago 60607, Illinois, USA
| | - Gordon C. Ibeanu
- Department of Pharmaceutical Science, North Carolina Central University, Durham 27707, North Carolina, USA
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Lin W, Cai X, Lin Y, Su W, Weng G, Chen L, Ding J, Cai Y. Identification of Immune-Related Gene Signature Model for Predicting Lung Cancer Survival and Response to Immunotherapy. Oncology 2024:1-19. [PMID: 39413743 DOI: 10.1159/000541990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Studies have shown that immune-related genes play a crucial role in tumor development and treatment. However, the specific roles and potential value of these genes in lung cancer patients are still not fully understood. Therefore, this study aims to establish a novel risk model based on immune-related genes for evaluating the prognostic risk and response to immune therapy in lung cancer patients. METHODS Gene expression and clinical data of lung cancer patients were retrieved from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, while immune-related genes were obtained from the ImmPort database. A risk signature model was developed using univariate Cox analysis and LASSO regression analysis. The prognostic value of the model and its response to immunotherapy were analyzed by survival analysis, immune infiltration analysis, and immunotherapy response analysis. RESULTS We have developed a risk signature model based on eight key immune-related genes, which can classify patients into high-risk and low-risk groups. The prognosis of the high-risk group was significantly lower than that of the low-risk group and was validated in multiple GEO datasets. The mutation frequency was lower in the low-risk group compared to the high-risk group (TP53: 55% vs. 65%; TTN: 52% vs. 60%; CSMD3: 34% vs. 45%). Futhermore, CD274 expression was lower in the low-risk patients, and the high-risk patients in the IMvigor210 cohort had lower survival. Immune infiltration analyses showed that the high-risk group was negatively correlated with the infiltration level of B cells, CD4+ T cells, and NK cells. Importantly, patients in the low-risk group exhibit significantly lower TIDE scores, suggesting that they are more responsive to immunotherapy. CONCLUSION Our study has established a novel and robust immune-related gene risk model that can assist in evaluating the prognostic risk and immune therapy response of lung cancer patients.
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Affiliation(s)
- Wenrong Lin
- Department of Ultrasound, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - XiaoJun Cai
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - YiJin Lin
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Weikun Su
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Guibin Weng
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Lin Chen
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jianming Ding
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yibin Cai
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
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Hou W, Zou Y, Li J, Jiang H, Li J, Wu J, Zhu S, Ding Y, Xu H, Jia F, Li X. Synergistic Therapy of Melanoma by Co-Delivery of Dacarbazine and Ferroptosis-Inducing Ursolic Acid Using Biomimetic Nanoparticles. ACS OMEGA 2024; 9:41532-41543. [PMID: 39398166 PMCID: PMC11465262 DOI: 10.1021/acsomega.4c05209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/15/2024]
Abstract
Melanoma is one of the most aggressive types of cancer and is prone to metastasis, making current clinical treatment quite difficult. The usage of the first-line medication dacarbazine (DTIC) for melanoma is limited due to harsh side effects, limited water solubility, and a short half-life. To tackle these disadvantages, polylactic acid-hydroxyacetic acid copolymer nanoparticles (NPs) loaded with dacarbazine and ursolic acid (NPs) were fabricated, which were further encapsulated with a red blood cell membrane (RNPs). MTT, apoptosis assay, wound healing assay, colony formation assay, and immunohistochemistry were used to assess the antitumor effect of NPs and RNPs. Ferroptosis evaluation was implemented using GSH detection and the malondialdehyde assay. We found that RNPs exhibited stability and biosafety in vitro and in vivo and achieved superior anticancer ability against xenograft tumors compared with single agents and NPs, which indicated the synergistic and biomimetic efficacy. Furthermore, ferroptotic activity was observed in RNPs-treated tumor cells, and ferroptosis inhibition could partially rescue melanoma cells from RNPs-induced cell death. Collectively, this study evaluated the potential of RNPs as a novel biomimetic nanomedicine for synergistic melanoma therapy by eliciting ferroptosis in tumor cells with both anticancer activity and biosafety.
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Affiliation(s)
- Wenjun Hou
- Department
of Dermatology, Nanjing Drum Tower Hospital, 321 Zhongshan Road, Nanjing 210008, China
| | - Yifan Zou
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 101 Longmian Avenue, Nanjing 211166, China
- Department
of General Surgery, The First Affiliated
Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Jie Li
- Department
of Geriatric Gastroenterology, The First
Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Hui Jiang
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Jinyu Li
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Jie Wu
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Senlin Zhu
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Yan Ding
- Department
of Geriatric Gastroenterology, The First
Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Huae Xu
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Feng Jia
- Department
of Neurosurgery, Yancheng No. 1 People’s Hospital, The Affiliated Yancheng First Hospital of Nanjing
University Medical School, 66 Renmin South Road, Yancheng 224008, China
| | - Xiaolin Li
- Department
of Geriatric Gastroenterology, The First
Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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Honkanen M, Narvi E, Ojala VK, Jokilammi A, Rantakari P, Kronqvist P, Kähäri VM, Veräjänkorva E, Kurppa KJ, Rahkila J, Ekambaram R, Savolainen J, Leino R, Elenius K. Immunomodulatory Synthetic Glycocluster Molecule Prevents Melanoma Growth In Vivo. Chembiochem 2024; 25:e202400264. [PMID: 38864514 DOI: 10.1002/cbic.202400264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/07/2024] [Accepted: 06/12/2024] [Indexed: 06/13/2024]
Abstract
Triacedimannose (TADM) is a synthetic trivalent acetylated glycocluster and a transmembrane macrophage activator independent of the mannose receptor. TADM induces Th1-type immune responses and suppresses Th2-type cytokines in acute and chronic allergic inflammation models in vivo. We, therefore, wanted to test whether TADM could also facilitate anti-tumour tissue responses similar to what has been observed for the immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4. A syngeneic mouse melanoma model was selected since metastatic melanoma has been successfully targeted by checkpoint inhibitors in the clinic. TADM inhibited the growth of B16 mouse melanoma tumours at levels comparable to an anti-PD-1 antibody. TADM-treated tumours encompassed significantly more apoptotic cells as measured by TUNEL staining, and interferon-gamma (IFN-γ) expression was increased in the spleens of TADM-treated mice compared to untreated controls. TADM-treated mice also demonstrated increased Ly6 C low monocytes and neutrophils in the spleens. However, TADM-treated tumours showed no discernible differences in infiltrating immune cells. TADM can alone suppress the growth of melanoma tumours. TADM likely activates M1 type macrophages, type N1 neutrophils, and CD8+ and Th1 T cells, suppressing the type 2 immune response milieu of melanoma tumour with a strong type 1 immune response.
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Affiliation(s)
- Meija Honkanen
- Institute of Biomedicine and MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, Finland
- Turku Graduate School of Molecular Medicine, University of Turku, Turku, Finland
| | - Elli Narvi
- Institute of Biomedicine and MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, Finland
| | - Veera K Ojala
- Institute of Biomedicine and MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, Finland
- Turku Graduate School of Molecular Medicine, University of Turku, Turku, Finland
- Turku Bioscience Center, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku, Finland
| | - Anne Jokilammi
- Institute of Biomedicine and MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, Finland
- Turku Bioscience Center, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku, Finland
| | - Pia Rantakari
- Turku Bioscience Center, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku, Finland
- InFLAMES Flagship, University of Turku and Åbo Akademi University, Turku, Finland
| | - Pauliina Kronqvist
- Department of Pathology, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, Turku, Finland
| | - Veli-Matti Kähäri
- Department of Dermatology, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland
- FICANWest Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Esko Veräjänkorva
- Plastic and General Surgery, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland
| | - Kari J Kurppa
- Institute of Biomedicine and MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, Finland
| | - Jani Rahkila
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, Henrikinkatu 2, Turku, Finland
| | - Ramesh Ekambaram
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, Henrikinkatu 2, Turku, Finland
| | - Johannes Savolainen
- Department of Pulmonary Diseases and Clinical Allergology, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland
| | - Reko Leino
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, Henrikinkatu 2, Turku, Finland
| | - Klaus Elenius
- Institute of Biomedicine and MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, Finland
- Turku Bioscience Center, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku, Finland
- Department of Oncology, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland
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Ohguro H, Watanabe M, Sato T, Nishikiori N, Umetsu A, Higashide M, Yano T, Suzuki H, Miyazaki A, Takada K, Uhara H, Furuhashi M, Hikage F. Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review. Cells 2024; 13:1549. [PMID: 39329734 PMCID: PMC11430518 DOI: 10.3390/cells13181549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 09/28/2024] Open
Abstract
Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases.
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Affiliation(s)
- Hiroshi Ohguro
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (M.W.); (N.N.); (A.U.); (M.H.)
| | - Megumi Watanabe
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (M.W.); (N.N.); (A.U.); (M.H.)
| | - Tatsuya Sato
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.S.); (T.Y.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Nami Nishikiori
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (M.W.); (N.N.); (A.U.); (M.H.)
| | - Araya Umetsu
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (M.W.); (N.N.); (A.U.); (M.H.)
| | - Megumi Higashide
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (M.W.); (N.N.); (A.U.); (M.H.)
| | - Toshiyuki Yano
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.S.); (T.Y.); (M.F.)
| | - Hiromu Suzuki
- Departments of Molecular Biology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan;
| | - Akihiro Miyazaki
- Departments of Oral Surgery, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan;
| | - Kohichi Takada
- Departments of Medical Oncology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan;
| | - Hisashi Uhara
- Departments of Dermatology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan;
| | - Masato Furuhashi
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.S.); (T.Y.); (M.F.)
| | - Fumihito Hikage
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (M.W.); (N.N.); (A.U.); (M.H.)
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Miao X, Guo Z, Zhang K, Chang J, Yang J, Miao G, Tian Y. Changes in mucosa‑associated lymphoid tissue 1 predicts therapeutic response and survival in patients with advanced melanoma receiving programmed cell death‑1 inhibitor monotherapy. Oncol Lett 2024; 28:433. [PMID: 39049986 PMCID: PMC11268090 DOI: 10.3892/ol.2024.14566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/19/2024] [Indexed: 07/27/2024] Open
Abstract
Advanced melanoma is an aggressive and dangerous form of skin cancer, and programmed cell death-1 (PD-1) inhibitors are recommended treatment options for patients with advanced melanoma. Mucosa-associated lymphoid tissue 1 (MALT1) impairs CD8+ T-cell activation to induce immune escape, leading to a reduction in the antitumor effect of PD-1 inhibitors. The present study aimed to assess the prognostic implication of MALT1 in patients with advanced melanoma receiving PD-1 inhibitor monotherapy. Blood MALT1 levels were assessed using reverse transcription-quantitative PCR in 20 healthy controls (HCs) after enrollment and in 49 patients with advanced melanoma before (T0), as well as 2 months (T1) and 4 months after (T2) PD-1 inhibitor monotherapy. The maximum level of MALT1 in HCs (3.100) was used as the cut-off in patients with advanced melanoma. MALT1 levels at T0 were significantly increased in patients with advanced melanoma compared with in HCs (P<0.001). In patients with advanced melanoma, MALT1 was significantly decreased from T0 to T2 (P<0.001). Objective response rate (ORR) and disease control rate (DCR) were 28.6 and 59.2%, respectively. MALT1 levels at T1 were significantly negatively associated with overall therapeutic response (P=0.001), ORR (P=0.009) and DCR (P=0.004). MALT1 levels at T2 were significantly inversely associated with overall therapeutic response (P=0.021) and ORR (P=0.036). Moreover, MALT1 levels >3.100 at T0 (P=0.027) and T1 (P=0.045) were significantly associated with shorter progression-free survival (PFS), and MALT1 levels >3.100 at T1 were significantly associated with a poor overall survival (OS; P=0.022). Multivariate Cox regression analysis demonstrated that MALT1 levels at T0 (>3.100 vs. ≤3.100) were significantly associated with a poor PFS [hazard ratio (HR)=2.248; P=0.037], and MALT1 levels at T1 (>3.100 vs. ≤3.100) were significantly associated with a poor OS (HR=4.332; P=0.007). In conclusion, MALT1 levels are reduced following PD-1 treatment, and a high MALT1 level is associated with a poor therapeutic response and shorter survival in patients with advanced melanoma receiving PD-1 inhibitor monotherapy.
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Affiliation(s)
- Xiaoyan Miao
- Department of Plastic Surgery, Affiliated Hospital of Hebei Engineering University, Handan, Hebei 056002, P.R. China
| | - Ziyi Guo
- Department of Burn and Plastic Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Kai Zhang
- Department of Orthopedics 1, Handan Central Hospital, Handan, Hebei 056000, P.R. China
| | - Jin Chang
- Department of Plastic Surgery, Affiliated Hospital of Hebei Engineering University, Handan, Hebei 056002, P.R. China
| | - Jianmin Yang
- Department of Plastic Surgery, Beijing Tsinghua Changgung Hospital, Beijing 102218, P.R. China
| | - Guoying Miao
- Department of Dermatology, Affiliated Hospital of Hebei Engineering University, Handan, Hebei 056002, P.R. China
| | - Yan Tian
- Department of Plastic Surgery, Affiliated Hospital of Hebei Engineering University, Handan, Hebei 056002, P.R. China
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Ghebrehiwet M, Pavlis J, Gomez-Meade C. Intralesional Talimogene Laherparepvec Immunotherapy for Melanoma: A Case Study. Cureus 2024; 16:e69605. [PMID: 39429342 PMCID: PMC11486653 DOI: 10.7759/cureus.69605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
Melanoma, characterized by its aggressive nature and tendency for metastasis, presents a significant challenge in clinical management. While surgical excision remains the gold standard for localized disease, therapeutic advancements for advanced stages are crucial. Oncolytic virotherapy, exemplified by Talimogene laherparepvec (T-VEC), offers a potential approach. Here, we present a 79-year-old male with advanced melanoma on the left distal thumb who opted for T-VEC therapy over surgical excision. Over 18 sessions, T-VEC demonstrated efficacy, resulting in lesion regression and no evidence of recurrence upon long-term monitoring. This case emphasizes the potential of T-VEC in advanced melanoma management, leveraging its dual mechanism targeting primary and metastatic lesions while harnessing immune response. Safety considerations and further investigations into potential interactions with other immunotherapies are warranted to optimize treatment strategies and ensure patient well-being. As oncolytic virotherapy continues to evolve, T-VEC stands as a potential option for the treatment of advanced melanoma.
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Affiliation(s)
- Merhawit Ghebrehiwet
- College of Medicine, Oklahoma State University Center for Health Sciences, Tulsa, USA
| | - Janelle Pavlis
- Dermatology, Oklahoma Cancer Specialists and Research Institute, Tulsa, USA
| | - Carlos Gomez-Meade
- Dermatology, Oklahoma Cancer Specialists and Research Institute, Tulsa, USA
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Lara-Vega I. Upgrading Melanoma Treatment: Promising Immunotherapies Combinations
in the Preclinical Mouse Model. CURRENT CANCER THERAPY REVIEWS 2024; 20:489-509. [DOI: 10.2174/0115733947263244231002042219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/27/2023] [Accepted: 08/25/2023] [Indexed: 01/03/2025]
Abstract
Background:
Melanoma, known for its high metastatic potential, does not respond well to
existing treatments in advanced stages. As a solution, immunotherapy-based treatments, including
anti-PD-1/L1 and anti-CTLA-4, have been developed and evaluated in preclinical mouse models to
overcome resistance. Although these treatments display the potential to suppress tumor growth, there
remains a crucial requirement for a thorough assessment of long-term efficacy in preventing metastasis
or recurrence and improving survival rates.
Methods:
From 2016 onwards, a thorough examination of combined immunotherapies for the treatment
of cutaneous melanoma in preclinical mouse models was conducted. The search was conducted
using MeSH Terms algorithms in PubMed®, resulting in the identification of forty-five studies that
met the rigorous inclusion criteria for screening.
Results:
The C57 mouse model bearing B16-melanoma has been widely utilized to assess the efficacy
of immunotherapies. The combination of therapies has demonstrated a synergistic impact, leading
to potent antitumor activity. One extensively studied method for establishing metastatic models involves
the intravenous administration of malignant cells, with several combined therapies under investigation.
The primary focus of evaluation has been on combined immunotherapies utilizing PD-
1/L1 and CTLA-4 blockade, although alternative immunotherapies not involving PD-1/L1 and
CTLA-4 blockade have also been identified. Additionally, the review provides detailed treatment regimens
for each combined approach.
Conclusion:
The identification of techniques for generating simulated models of metastatic melanoma
and investigating various therapeutic combinations will greatly aid in evaluating the overall systemic
efficacy of immunotherapy. This will be especially valuable for conducting short-term preclinical
experiments that have the potential for clinical studies.
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Affiliation(s)
- Israel Lara-Vega
- National School of Biological Sciences, IPN. Av. Wilfrido Massieu s/n, Professional Unit Adolfo Lopez Mateos, Mexico
City, CP 07738, Mexico
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40
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Arghidash F, Javid-Naderi MJ, Gheybi F, Gholamhosseinian H, Kesharwani P, Sahebkar A. Exploring the multifaceted effects of silymarin on melanoma: Focusing on the role of lipid-based nanocarriers. J Drug Deliv Sci Technol 2024; 99:105950. [DOI: 10.1016/j.jddst.2024.105950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Xiao A, Yin L, Chen T, Qian H. Lipo/TK-CDN/TPP/Y6 nanoparticles inhibit cutaneous melanoma formation. J Drug Target 2024; 32:931-940. [PMID: 38838039 DOI: 10.1080/1061186x.2024.2365243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/07/2024]
Abstract
Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumour immunity. Nevertheless, the systemic delivery of STING agonists to the tumour presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal therapy (PTT)/photodynamic therapy (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumours were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumour growth. Exploration of the mechanism of anti-tumour action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumour immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumour sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumours.
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Affiliation(s)
- Anju Xiao
- Department of Dermatology and Venereology, Dejiang County People's Hospital, Affiliated to Zunyi Medical University, Dejiang, China
| | - Li Yin
- Department of Pathology, Dejiang County People's Hospital, Affiliated to Zunyi Medical University, Dejiang, China
| | - Ting Chen
- Department of Clinical Medicine, Dejiang County People's Hospital, Affiliated to Zunyi Medical University, Dejiang, China
| | - Huiling Qian
- Department of Endocrinology, Dejiang County People's Hospital, Affiliated to Zunyi Medical University, Dejiang, China
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Benedusi M, Lee H, Lim Y, Valacchi G. Oxidative State in Cutaneous Melanoma Progression: A Question of Balance. Antioxidants (Basel) 2024; 13:1058. [PMID: 39334716 PMCID: PMC11428248 DOI: 10.3390/antiox13091058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/02/2024] [Accepted: 08/28/2024] [Indexed: 09/30/2024] Open
Abstract
Reactive oxygen species (ROS) are highly bioactive molecules involved not only in tissue physiology but also in the development of different human conditions, including premature aging, cardiovascular pathologies, neurological and neurodegenerative disorders, inflammatory diseases, and cancer. Among the different human tumors, cutaneous melanoma, the most aggressive and lethal form of skin cancer, is undoubtedly one of the most well-known "ROS-driven tumor", of which one of the main causes is represented by ultraviolet (UV) rays' exposure. Although the role of excessive ROS production in melanoma development in pro-tumorigenic cell fate is now well established, little is known about its contribution to the progression of the melanoma metastatic process. Increasing evidence suggests a dual role of ROS in melanoma progression: excessive ROS production may enhance cellular growth and promote therapeutic resistance, but at the same time, it can also have cytotoxic effects on cancer cells, inducing their apoptosis. In this context, the aim of the present work was to focus on the relationship between cell redox state and the signaling pathways directly involved in the metastatic processes. In addition, oxidative or antioxidant therapeutic strategies for metastatic melanoma were also reviewed and discussed.
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Affiliation(s)
- Mascia Benedusi
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy
| | - Heaji Lee
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Yunsook Lim
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Giuseppe Valacchi
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea
- Plants for Human Health Institute, NC Research Campus, NC State University, Kannapolis, NC 28081, USA
- Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy
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Janka EA, Szabó IL, Kollár S, Toka-Farkas T, Ványai B, Várvölgyi T, Kapitány A, Shabu H, Szegedi A, Emri G. Prognostic Role of Clinicopathological Characteristics and Serum Markers in Metastatic Melanoma Patients Treated with BRAF and MEK Inhibitors. Cancers (Basel) 2024; 16:2981. [PMID: 39272837 PMCID: PMC11393897 DOI: 10.3390/cancers16172981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Prognostic studies can provide important information about disease biology and improve the use of biomarkers to optimize treatment decisions. METHODS A total of 199 patients with advanced melanoma treated with BRAF + MEK inhibitors were included in our single-center retrospective study. We analyzed the risk of progression and death using multivariate Cox proportional hazard models. The predictive effect of prognostic factors on progression-free survival (PFS) was evaluated in ROC analysis. RESULTS We found that primary tumor localization, Clark level, pT category, baseline M stage and baseline serum S100B are independent and significant prognostic factors for PFS. The discriminative power of the combination of these factors was excellent for predicting 18 month PFS (AUC 0.822 [95% CI 0.727; 0.916], p < 0.001). Primary tumor localization on the extremities, Clark level V, baseline M1c stage or M1d stage, and elevated baseline serum S100B and LDH levels were independently and significantly associated with unfavorable overall survival (OS). CONCLUSION Baseline M stage and serum S100B appear to be independent prognostic factors for both PFS and OS in melanoma patients treated with BRAF + MEK inhibitors. We newly identified significant and independent prognostic effects of primary tumor localization and Clark level on survival that warrant further investigation.
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Affiliation(s)
- Eszter Anna Janka
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Imre Lőrinc Szabó
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Sándor Kollár
- Institute of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
| | - Tünde Toka-Farkas
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Beatrix Ványai
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Tünde Várvölgyi
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Anikó Kapitány
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Hibah Shabu
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Andrea Szegedi
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Gabriella Emri
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
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Kolathur KK, Nag R, Shenoy PV, Malik Y, Varanasi SM, Angom RS, Mukhopadhyay D. Molecular Susceptibility and Treatment Challenges in Melanoma. Cells 2024; 13:1383. [PMID: 39195270 DOI: 10.3390/cells13161383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/15/2024] [Accepted: 08/17/2024] [Indexed: 08/29/2024] Open
Abstract
Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitor resistance in melanoma.
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Affiliation(s)
- Kiran Kumar Kolathur
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Radhakanta Nag
- Department of Microbiology, College of Basic Science & Humanities, Odisha University of Agriculture & Technology (OUAT), Bhubaneswar 751003, Odisha, India
| | - Prathvi V Shenoy
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Yagya Malik
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Sai Manasa Varanasi
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Ramcharan Singh Angom
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
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Yang P, Jiang Y, Chen R, Yang J, Liu M, Huang X, Xu G, Hao R. Prognostic and immune infiltration implications of SIGLEC9 in SKCM. Diagn Pathol 2024; 19:112. [PMID: 39153970 PMCID: PMC11330613 DOI: 10.1186/s13000-024-01536-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/12/2024] [Indexed: 08/19/2024] Open
Abstract
The occurrence and progression of skin cutaneous melanoma (SKCM) is strongly associated with immune cells infiltrating the tumor microenvironment (TME). This study examined the expression, prognosis, and immune relevance of SIGLEC9 in SKCM using multiple online databases. Analysis of the GEPIA2 and Ualcan databases revealed that SIGLEC9 is highly expressed in SKCM, and patients with high SIGLEC9 expression had improved overall survival (OS). Furthermore, the mutation rate of SIGLEC9 in SKCM patients was found to be 5.41%, the highest observed. The expression of SIGLEC9 was positively correlated with macrophages, neutrophils and B cells, CD8 + T cells, CD4 + T cells, and dendritic cells, according to TIMER. Based on TCGA-SKCM data, we verified that high SIGLEC9 expression is closely associated with a good prognosis for SKCM patients, including overall survival, progression-free interval, and disease-specific survival. This positive prognosis could be due to the infiltration of immune cells into the TME. Additionally, our analysis of single-cell transcriptome data revealed that SIGLEC9 not only played a role in the normal skin immune microenvironment, but is also highly expressed in immune cell subpopulations of SKCM patients, regulating the immune response to tumors. Our findings suggest that the close association between SIGLEC9 and SKCM prognosis is primarily mediated by its effect on the tumor immune microenvironment.
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Affiliation(s)
- Peipei Yang
- Department of Dermatology, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China
| | - Yunhui Jiang
- Department of Pathology, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China
| | - Rong Chen
- Department of Clinical Laboratory, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China
| | - Junhan Yang
- Department of Dermatology, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China
| | - Mengting Liu
- Department of Dermatology, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China
| | - Xieping Huang
- Department of Dermatology, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China
| | - Ganglin Xu
- Department of Dermatology, Jingmen People'S Hospital &, Jingchu University of Technology Affiliated Central Hospital, Jingmen, 448000, China.
| | - Rui Hao
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China.
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Xiao L, He R, Hu K, Song G, Han S, Lin J, Chen Y, Zhang D, Wang W, Peng Y, Zhang J, Yu P. Exploring a specialized programmed-cell death patterns to predict the prognosis and sensitivity of immunotherapy in cutaneous melanoma via machine learning. Apoptosis 2024; 29:1070-1089. [PMID: 38615305 DOI: 10.1007/s10495-024-01960-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2024] [Indexed: 04/15/2024]
Abstract
The mortality and therapeutic failure in cutaneous melanoma (CM) are mainly caused by wide metastasis and chemotherapy resistance. Meanwhile, immunotherapy is considered a crucial therapy strategy for CM patients. However, the efficiency of currently available methods and biomarkers in predicting the response of immunotherapy and prognosis of CM is limited. Programmed cell death (PCD) plays a significant role in the occurrence, development, and therapy of various malignant tumors. In this research, we integrated fourteen types of PCD, multi-omics data from TCGA-SKCM and other cohorts in GEO, and clinical CM patients to develop our analysis. Based on significant PCD patterns, two PCD-related CM clusters with different prognosis, tumor microenvironment (TME), and response to immunotherapy were identified. Subsequently, seven PCD-related features, especially CD28, CYP1B1, JAK3, LAMP3, SFN, STAT4, and TRAF1, were utilized to establish the prognostic signature, namely cell death index (CDI). CDI accurately predicted the response to immunotherapy in both CM and other cancers. A nomogram with potential superior predictive ability was constructed, and potential drugs targeting CM patients with specific CDI have also been identified. Given all the above, a novel CDI gene signature was indicated to predict the prognosis and exploit precision therapeutic strategies of CM patients, providing unique opportunities for clinical intelligence and new management methods for the therapy of CM.
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Affiliation(s)
- Leyang Xiao
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, People's Republic of China
| | - Ruifeng He
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, People's Republic of China
| | - Kaibo Hu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, People's Republic of China
| | - Gelin Song
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, People's Republic of China
| | - Shengye Han
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, People's Republic of China
| | - Jitao Lin
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Yixuan Chen
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, 999077, Hong Kong, Hong Kong
| | - Wuming Wang
- Department of Thoracic Surgery, Jiangxi Provincial Chest Hospital, Nanchang, 330006, People's Republic of China
| | - Yating Peng
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, People's Republic of China.
| | - Peng Yu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, People's Republic of China.
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Zhu T, Zong C, Li Y, Jia S, Shi H, Tian H, Rao Y, Zhang X, Ge S, Fan X, Li Y, Jia R, Xu S. High-risk histopathologic features in local advanced conjunctival melanoma. Acta Ophthalmol 2024; 102:e851-e861. [PMID: 38420891 DOI: 10.1111/aos.16662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 01/11/2024] [Accepted: 02/10/2024] [Indexed: 03/02/2024]
Abstract
PURPOSE To identify high-risk histopathologic and molecular features of local recurrence, nodal metastasis, distant metastasis (DM) and disease-specific death (DSD) in conjunctival melanoma (CoM). METHODS Ninety patients with pathologically diagnosed CoM between 2008 and 2023 were enrolled. Immunohistochemistry staining of BRAFV600E, NRASQ61R, CD117, PD-1 and PD-L1 was performed in 65 and 45 patients, respectively. Cox regression and Kaplan-Meier survival analysis were conducted to identify risk factors for local recurrence, nodal metastasis, DM and DSD. RESULTS Pathologically, ulceration (hazard ratio [HR]: 3.170; 95% CI: 1.312-7.659; p = 0.01) and regression (HR: 3.196; 95% CI: 1.094-9.335; p = 0.034) were risk factors for DM. Tumour thickness ≥ 4 mm (HR: 4.889; 95% CI: 1.846-12.946; p = 0.001) and regression (HR: 4.011; 95% CI: 1.464-10.991; p = 0.007) were risk factors for DSD. For patients with tumour thickness < 4 mm, the presence of ulceration indicated a higher risk of nodal metastasis (log-rank p = 0.0011), DM (log-rank p = 0.00051) and DSD (log-rank p = 0.02). Patients with regression (+)/tumour-infiltrating lymphocytes (TILs) (+) had a higher risk for DM (log-rank p = 0.011) and DSD (log-rank p = 0.0032). Molecularly, the positive rate of BRAFV600E, NRASQ61R, CD117, PD-1 and PD-L1 was 40.00% (26/65), 43.08% (28/65), 70.77% (46/65), 46.67% (21/45) and 28.89% (13/45), respectively. Positive BRAFV600E was identified as an independent risk factor for DM (HR: 2.533; 95% CI: 1.046-6.136, p = 0.039). The expression level of BRAFV600E was positively correlated with vascular invasion (p = 0.01), as well as the expression levels of PD-1 (p = 0.038) and PD-L1 (p = 0.049). CONCLUSIONS Tumour thickness ≥ 4 mm, ulceration, the coexistence of regression and TILs, and positive BRAFV600E were risk factors for poor prognosis of CoM patients. Besides, expression level of BRAFV600E was positively correlated with the expression levels of PD-1 and PD-L1.
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Affiliation(s)
- Tianyu Zhu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunyan Zong
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongyun Li
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shichong Jia
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hanhan Shi
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Tian
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yamin Rao
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Zhang
- Department of Implant Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yimin Li
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Renbing Jia
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiqiong Xu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Bialves TS, Bastos LL, Parra JAA, Moysés MN, Marques E, de Castro Pimenta AM, Quintela FM, Mariano DCB, Carvalho FC, de Melo-Minardi RC, Boyle RT. Interaction of DisBa01 peptide from Bothrops alternatus venom with BRAF melanoma receptors: Modeling and molecular docking. Int J Biol Macromol 2024; 274:133283. [PMID: 38909731 DOI: 10.1016/j.ijbiomac.2024.133283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 06/12/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Metastatic melanoma is highly aggressive and challenging, often leading to a grim prognosis. Its progression is swift, especially when mutations like BRAFV600E continuously activate pathways vital for cell growth and survival. Although several treatments target this mutation, resistance typically emerges over time. In recent decades, research has underscored the potential of snake venoms and peptides as bioactive substances for innovative drugs, including anti-coagulants, anti-microbial, and anti-cancer agents. Leveraging this knowledge, we propose employing a bioinformatics simulation approach to: a) Predict how well a peptide (DisBa01) from Bothrops alternatus snake venom binds to the melanoma receptor BRAFV600E via Molecular Docking. b) Identify the specific peptide binding sites on receptors and analyze their proximity to active receptor sites. c) Evaluate the behavior of resulting complexes through molecular dynamics simulations. d) Assess whether this peptide qualifies as a candidate for anti-melanoma therapy. Our findings reveal that DisBa01 enhances stability in the BRAFV600E melanoma receptor structure by binding to its RGD motif, an interaction absent in the BRAF WT model. Consequently, both docking and molecular dynamics simulations suggest that DisBa01 shows promise as a BRAFV600E inhibitor.
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Affiliation(s)
- Tatiane Senna Bialves
- Graduate Program in Physiological Sciences (PPGCF), Federal University of Rio Grande - FURG, Av. Italy, s/n - km 8 - Carreiros, Rio Grande, Rio Grande do Sul, Brazil.
| | - Luana Luiza Bastos
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - John Alexanders Amaya Parra
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maurício Nogueira Moysés
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Edleusa Marques
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Adriano Monteiro de Castro Pimenta
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Fernando Marques Quintela
- Instituto Nacional de Pesquisas do Pantanal- Museu Paraense Emílio Goeldi, Av. Magalhães Barata, 376, Belém, Pará, Brazil
| | - Diego César Batista Mariano
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Frederico Chaves Carvalho
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Raquel C de Melo-Minardi
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Robert Tew Boyle
- Graduate Program in Physiological Sciences (PPGCF), Federal University of Rio Grande - FURG, Av. Italy, s/n - km 8 - Carreiros, Rio Grande, Rio Grande do Sul, Brazil
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Magrill J, Moldoveanu D, Gu J, Lajoie M, Watson IR. Mapping the single cell spatial immune landscapes of the melanoma microenvironment. Clin Exp Metastasis 2024; 41:301-312. [PMID: 38217840 PMCID: PMC11374855 DOI: 10.1007/s10585-023-10252-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 11/27/2023] [Indexed: 01/15/2024]
Abstract
Melanoma is a highly immunogenic malignancy with an elevated mutational burden, diffuse lymphocytic infiltration, and one of the highest response rates to immune checkpoint inhibitors (ICIs). However, over half of all late-stage patients treated with ICIs will either not respond or develop progressive disease. Spatial imaging technologies are being increasingly used to study the melanoma tumor microenvironment (TME). The goal of such studies is to understand the complex interplay between the stroma, melanoma cells, and immune cell-types as well as their association with treatment response. Investigators seeking a better understanding of the role of cell location within the TME and the importance of spatial expression of biomarkers are increasingly turning to highly multiplexed imaging approaches to more accurately measure immune infiltration as well as to quantify receptor-ligand interactions (such as PD-1 and PD-L1) and cell-cell contacts. CyTOF-IMC (Cytometry by Time of Flight - Imaging Mass Cytometry) has enabled high-dimensional profiling of melanomas, allowing researchers to identify complex cellular subpopulations and immune cell interactions with unprecedented resolution. Other spatial imaging technologies, such as multiplexed immunofluorescence and spatial transcriptomics, have revealed distinct patterns of immune cell infiltration, highlighting the importance of spatial relationships, and their impact in modulating immunotherapy responses. Overall, spatial imaging technologies are just beginning to transform our understanding of melanoma biology, providing new avenues for biomarker discovery and therapeutic development. These technologies hold great promise for advancing personalized medicine to improve patient outcomes in melanoma and other solid malignancies.
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Affiliation(s)
- Jamie Magrill
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
- Department of Human Genetics, McGill University, Montréal, QC, Canada
| | - Dan Moldoveanu
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
| | - Jiayao Gu
- Department of Human Genetics, McGill University, Montréal, QC, Canada
| | - Mathieu Lajoie
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada
| | - Ian R Watson
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC, Canada.
- Department of Human Genetics, McGill University, Montréal, QC, Canada.
- Department of Biochemistry, McGill University, Montréal, QC, Canada.
- Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
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Wang W, Liu P, Ma J, Li J, Leng L. Establishment of a CD8+ T cells-related prognostic risk model for acral melanoma based on single-cell and bulk RNA sequencing. Skin Res Technol 2024; 30:e13900. [PMID: 39093712 PMCID: PMC11296306 DOI: 10.1111/srt.13900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 07/20/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND CD8+ T cells have been recognized as crucial factors in the prognosis of melanoma. However, there is currently a lack of gene markers that accurately describe their characteristics and functions in acral melanoma (AM), which hinders the development of personalized medicine. METHODS Firstly, we explored the composition differences of immune cells in AM using single-cell RNA sequencing (scRNA-seq) data and comprehensively characterized the immune microenvironment of AM in terms of composition, developmental differentiation, function, and cell communication. Subsequently, we constructed and validated a prognostic risk scoring model based on differentially expressed genes (DEGs) of CD8+ T cells using the TCGA-SKCM cohort through Lasso-Cox method. Lastly, immunofluorescence staining was performed to validate the expression of four genes (ISG20, CCL4, LPAR6, DDIT3) in AM and healthy skin tissues as included in the prognostic model. RESULTS The scRNA-seq data revealed that memory CD8+ T cells accounted for the highest proportion in the immune microenvironment of AM, reaching 70.5%. Cell-cell communication analysis showed extensive communication relationships among effector CD8+ T cells. Subsequently, we constructed a prognostic scoring model based on DEGs derived from CD8+ T cell sources. Four CD8+ T cell-related genes were included in the construction and validation of the prognostic model. Additionally, immunofluorescence results demonstrated that ISG20 and CCL4 were downregulated, while LPAR6 and DDIT3 were upregulated in AM tissues compared to normal skin tissues. CONCLUSION Identifying biomarkers based on the expression levels of CD8+ T cell-related genes may be an effective approach for establishing prognostic models in AM patients. The independently prognostic risk evaluation model we constructed provides new insights and theoretical support for immunotherapy in AM.
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Affiliation(s)
- Wenwen Wang
- Department of DermatologyPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Stem Cell and Regenerative Medicine LabDepartment of Medical Science Research CenterState Key Laboratory for ComplexSevere, and Rare DiseasesCenter for Translational MedicinePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Pu Liu
- Chongqing Key Laboratory on Big Data for Bio IntelligenceChongqing University of Posts and TelecommunicationsChongqingChina
- State Key Laboratory of Medical ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijingChina
| | - Jie Ma
- State Key Laboratory of Medical ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijingChina
| | - Jun Li
- Department of DermatologyPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ling Leng
- Stem Cell and Regenerative Medicine LabDepartment of Medical Science Research CenterState Key Laboratory for ComplexSevere, and Rare DiseasesCenter for Translational MedicinePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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