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Sun J, Chen Y, Xu Z, Wang W, Li P. Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities. J Transl Med 2025; 23:315. [PMID: 40075484 PMCID: PMC11900264 DOI: 10.1186/s12967-025-06282-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: 11/29/2024] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by a complex interplay of genetic, environmental, and immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, the Notch signaling pathway is instrumental in governing cell fate decisions, tissue renewal, homeostasis, and immune cell development. As a highly conserved mechanism, Notch signaling not only modulates tumor cell behavior but also shapes the immune landscape within the tumor microenvironment (TME). Aberrant Notch signaling in CRC fosters immune evasion and tumor progression through its effects on the balance and functionality of immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Elevated Notch pathway activation correlates with advanced clinicopathological features and poorer clinical outcomes, highlighting its relevance as both a prognostic biomarker and a therapeutic target. Therapeutic approaches aimed at inhibiting the Notch pathway, such as γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) in combination with other therapies, have demonstrated promising efficacy in preclinical and clinical settings. This review examines the impact of Notch signaling on CRC immunity, elucidating its regulatory mechanisms within immune cells and its role in promoting tumor progression. Additionally, this review discusses therapeutic strategies targeting Notch signaling, including GSIs, mAbs, and potential combination therapies designed to overcome resistance and improve patient outcomes. By elucidating the multifaceted role of Notch within the CRC TME, this review underscores its potential as a target for innovative therapeutic strategies.
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Affiliation(s)
- Jiachun Sun
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, 471003, China
| | - Yi Chen
- Department of Children's gastroenterology, Anhui Children's Hospital, Hefei, Anhui, 230000, China
| | - Ziyi Xu
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, 471003, China
| | - Weizheng Wang
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, 471003, China
| | - Penghui Li
- Department of Gastrointestinal surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang, Henan, 471000, China.
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Cheng WM, Li PC, Nguyen MTB, Lin YT, Huang YT, Cheng TS, Nguyen TH, Tran TH, Huang TY, Hoang TH, Chen SY, Chu YC, Wu CW, Lee MF, Chiou YS, Liu HS, Hong YR, Chang PMH, Hu YF, Chang YC, Lai JM, Huang CYF. Repurposing pitavastatin and atorvastatin to overcome chemoresistance of metastatic colorectal cancer under high glucose conditions. Cancer Cell Int 2025; 25:79. [PMID: 40050889 PMCID: PMC11887183 DOI: 10.1186/s12935-025-03712-2] [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: 04/04/2024] [Accepted: 02/22/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) poses a significant clinical challenge because of drug resistance, which can adversely impact patient outcomes. Recent research has shown that abnormalities within the tumor microenvironment, especially hyperglycemia, play a crucial role in promoting metastasis and chemoresistance, and thereby determine the overall prognosis of patients with advanced CRC. METHODS This study employs data mining and consensus molecular subtype (CMS) techniques to identify pitavastatin and atorvastatin as potential agents for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained under either low or high glucose conditions were established and utilized to assess the cytotoxic effects of pitavastatin and atorvastatin, both with and without 5-fluorouracil (5-FU). CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of pitavastatin and atorvastatin. RESULTS A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. The CMS4 CRC cell line SW480 (SW480-HG) was established and cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. Pitavastatin and atorvastatin could inhibit cell proliferation and 3D spheroid formation of CMS4 CRC cells under high glucose conditions. In addition, both pitavastatin and atorvastatin can synergistically promote the 5-FU-mediated cytotoxic effect and inhibit the growth of 5-FU-resistant CRC cells. Mechanistically, pitavastatin and atorvastatin can induce apoptosis and synergistically promote the 5-FU-mediated cytotoxic effect by activating autophagy, as well as the PERK/ATF4/CHOP signaling pathway while decreasing YAP expression. CONCLUSION This study highlights the biomarker-guided precision medicine strategy for drug repurposing. Pitavastatin and atorvastatin could be used to assist in the treatment of advanced CRC, particularly with CMS4 subtype CRC patients who also suffer from hyperglycemia. Pitavastatin, with an achievable dosage used for clinical interventions, is highly recommended for a novel CRC therapeutic strategy.
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Affiliation(s)
- Wei-Ming Cheng
- Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Department of Urology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Division of Urology, Department of Surgery, Zhongxiao Branch, Taipei City Hospital, Taipei, 115, Taiwan
| | - Po-Chen Li
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Minh Tran-Binh Nguyen
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
| | - Yu-Teng Lin
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Yu-Tang Huang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Tai-Shan Cheng
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City, 220, Taiwan
| | - Thi-Huong Nguyen
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Institute of Biotechnology and Food Technology, Thai Nguyen University of Agriculture and Forestry, Thai Nguyen, Vietnam
| | - Thu-Ha Tran
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 112, Taiwan
| | - Tzu-Yi Huang
- Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Thu-Huyen Hoang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Sin-Yu Chen
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Yu-Chieh Chu
- Taipei First Girls High School, Taipei, 110, Taiwan
| | - Chih-Wei Wu
- Taipei First Girls High School, Taipei, 110, Taiwan
| | - Ming-Fen Lee
- Department of Nutrition, China Medical University, Taichung, 406, Taiwan
| | - Yi-Shiou Chiou
- Master Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Hsiao-Sheng Liu
- Medical Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- 13 M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Center for Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung City, 807, Taiwan
| | - Yi-Ren Hong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Peter Mu-Hsin Chang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, 112, Taiwan
| | - Yu-Feng Hu
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan
| | - Ying-Chih Chang
- Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan
- Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA
| | - Jin-Mei Lai
- Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, 242, Taiwan.
| | - Chi-Ying F Huang
- Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
- Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Chong Hin Loon Memorial Cancer and Biotherapy Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
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Ying L, Zhang L, Chen Y, Huang C, Zhou J, Xie J, Liu L. Predicting immunotherapy prognosis and targeted therapy sensitivity of colon cancer based on a CAF-related molecular signature. Sci Rep 2025; 15:6387. [PMID: 39984646 PMCID: PMC11845748 DOI: 10.1038/s41598-025-90899-z] [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: 11/12/2024] [Accepted: 02/17/2025] [Indexed: 02/23/2025] Open
Abstract
The role of cancer-associated fibroblasts (CAFs) in modulating the tumor microenvironment (TME) is gaining attention, yet their impact on prognosis and therapeutic response in colon cancer remains unclear. Here, we identified genes associated with CAF infiltration via weighted gene co-expression network analysis (WGCNA) utilizing data from The Cancer Genome Atlas (TCGA) and GSE39582 cohorts. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct CAF molecular signatures (CAFscore). Patients were categorized into high and low CAFscore groups to analyze clinicopathological traits, somatic mutations, immune evasion, and treatment responses. In this study, a total of 244 genes were correlated with CAF infiltration, with 11 linked to overall survival. Notably, FSTL3, CRIP2, and SLC2A3 were selected for the CAFscore. A higher CAFscore was associated with poorer prognoses, increased malignancy, and therapeutic resistance, particularly among patients with high tumor mutation burden and microsatellite instability. Furthermore, elevated FSTL3 expression was associated with reduced CD8+ T cell infiltration, indicating a suppressive TME. Mechanistically, CAFs may promote immune evasion via NAMPT ligand-receptor interactions based on single-cell RNA sequencing data. Thus, the CAFscore is crucial for personalizing treatment strategies and identifying patients who require more aggressive management.
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Affiliation(s)
- Leqian Ying
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Lu Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Yanping Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Chunchun Huang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Jingyi Zhou
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Jinbing Xie
- Department of Radiology, Nurturing Center of Jiangsu Province for the State Laboratory of AI Imaging and Interventional Radiology, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Lin Liu
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China.
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Coelho D, Estêvão D, Oliveira MJ, Sarmento B. Radioresistance in rectal cancer: can nanoparticles turn the tide? Mol Cancer 2025; 24:35. [PMID: 39885557 PMCID: PMC11784129 DOI: 10.1186/s12943-025-02232-x] [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: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Rectal cancer accounts for over 35% of the worldwide colorectal cancer burden representing a distinctive subset of cancers from those arising in the colon. Colorectal cancers exhibit a continuum of traits that differ with their location in the large intestine. Due to anatomical and molecular differences, rectal cancer is treated differently from colon cancer, with neoadjuvant chemoradiotherapy playing a pivotal role in the control of the locally advanced disease. However, radioresistance remains a major obstacle often correlated with poor prognosis. Multifunctional nanomedicines offer a promising approach to improve radiotherapy response rates, as well as to increase the intratumoral concentration of chemotherapeutic agents, such as 5-Fluorouracil. Here, we revise the main molecular differences between rectal and colon tumors, exploring the complex orchestration beyond rectal cancer radioresistance and the most promising nanomedicines reported in the literature to improve neoadjuvant therapy response rates.
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Affiliation(s)
- Diogo Coelho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal
| | - Diogo Estêvão
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute, Ghent University, Ghent, Belgium
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal.
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Carranza FG, Diaz FC, Ninova M, Velazquez-Villarreal E. Current state and future prospects of spatial biology in colorectal cancer. Front Oncol 2024; 14:1513821. [PMID: 39711954 PMCID: PMC11660798 DOI: 10.3389/fonc.2024.1513821] [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] [Received: 10/19/2024] [Accepted: 11/15/2024] [Indexed: 12/24/2024] Open
Abstract
Over the past century, colorectal cancer (CRC) has become one of the most devastating cancers impacting the human population. To gain a deeper understanding of the molecular mechanisms driving this solid tumor, researchers have increasingly turned their attention to the tumor microenvironment (TME). Spatial transcriptomics and proteomics have emerged as a particularly powerful technology for deciphering the complexity of CRC tumors, given that the TME and its spatial organization are critical determinants of disease progression and treatment response. Spatial transcriptomics enables high-resolution mapping of the whole transcriptome. While spatial proteomics maps protein expression and function across tissue sections. Together, they provide a detailed view of the molecular landscape and cellular interactions within the TME. In this review, we delve into recent advances in spatial biology technologies applied to CRC research, highlighting both the methodologies and the challenges associated with their use, such as the substantial tissue heterogeneity characteristic of CRC. We also discuss the limitations of current approaches and the need for novel computational tools to manage and interpret these complex datasets. To conclude, we emphasize the importance of further developing and integrating spatial transcriptomics into CRC precision medicine strategies to enhance therapeutic targeting and improve patient outcomes.
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Affiliation(s)
- Francisco G. Carranza
- Department of Integrative Translational Sciences, City of Hope, Beckman Research Institute, Duarte, CA, United States
| | - Fernando C. Diaz
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States
| | - Maria Ninova
- Department of Biochemistry, University of California, Riverside, Riverside, CA, United States
| | - Enrique Velazquez-Villarreal
- Department of Integrative Translational Sciences, City of Hope, Beckman Research Institute, Duarte, CA, United States
- City of Hope Comprehensive Cancer Center, Duarte, CA, United States
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Ding X, Huang H, Fang Z, Jiang J. From Subtypes to Solutions: Integrating CMS Classification with Precision Therapeutics in Colorectal Cancer. Curr Treat Options Oncol 2024; 25:1580-1593. [PMID: 39589648 DOI: 10.1007/s11864-024-01282-5] [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: 11/11/2024] [Indexed: 11/27/2024]
Abstract
OPINION STATEMENT The biological heterogeneity of colorectal cancer makes its molecular characteristics essential for therapeutic decision-making and prognostic evaluation. Recent advancements in consensus molecular subtyping, based on gene expression profiling, have provided deeper insights into the heterogeneity of CRC. CMS1, known as the immune subtype, is characterized by robust immune activity and microsatellite instability. CMS2, the canonical subtype, exhibits significant activation of the WNT and MYC signaling pathways. CMS3, the metabolic subtype, features unique metabolic dysregulations. CMS4, the mesenchymal subtype, is recognized for its stromal invasion and angiogenesis, which are associated with a poorer prognosis. This review delivers a thorough analysis of the biological and clinical responses of each CMS subtype in colorectal cancer, highlighting their therapeutic vulnerabilities. It integrates data and clinical trial results to suggest potential new therapies for each subtype. The goal is to improve therapeutic efficacy, minimize treatment disparities, and offer CRC patients more precise treatment options.
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Affiliation(s)
- Xinyi Ding
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Hao Huang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Zhang Fang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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Chowdhury S, Xiu J, Ribeiro JR, Nicolaides T, Zhang J, Korn WM, Poorman KA, Lenz HJ, Marshall JL, Oberley MJ, Sledge GW, Spetzler D, Kopetz S, Shen JP. Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors. Br J Cancer 2024; 131:1328-1339. [PMID: 39227409 PMCID: PMC11473766 DOI: 10.1038/s41416-024-02826-0] [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: 11/29/2023] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 09/05/2024] Open
Abstract
BACKGROUND We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939). METHODS The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant). RESULTS CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer TOT with anti-EGFR antibodies (cetuximab and panitumumab). When restricting to only CMS2, there was no significant difference in TOT between right- versus left-sided tumors. CMS1 tumors were associated with a longer median TOT with pembrolizumab relative to other CMS groups, even when analyzing only microsatellite stable (MSS) tumors. DISCUSSION A WTS-based CMS classifier allowed investigation of a large multi-institutional clinico-genomic mCRC cohort, suggesting anti-EGFR therapy benefit for right-sided RAS-WT CMS2 tumors and immune checkpoint inhibitor benefit for MSS CMS1. Routine CMS classification of CRC provides important treatment associations that should be further investigated.
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Affiliation(s)
- Saikat Chowdhury
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | | | - W Michael Korn
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | | | - Heinz-Josef Lenz
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - John L Marshall
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | | | | | | | - Scott Kopetz
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John Paul Shen
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Xia H, Li Z, Lin Y, Lin Y, Zeng L, Xu B, Yao Q, Zheng R. Validation of a genome-based model for adjusting radiotherapy dose (GARD) in patients with locally advanced rectal cancer. Sci Rep 2024; 14:21572. [PMID: 39284851 PMCID: PMC11405410 DOI: 10.1038/s41598-024-72818-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 09/10/2024] [Indexed: 09/20/2024] Open
Abstract
Neoadjuvant radiotherapy is the standard care of locally advanced rectal cancer. Although a majority of patients received the same dose, the curative efficacy varies among individuals. In recent years, cancer treatment has entered the era of precise medical care, and how to identify patients for proper treatment by molecular signature is an important path of individualized therapy. This study aimed to establish and validate a genome-based model for adjusting radiation dose (GARD) for Chinese locally advanced rectal cancer through gene expression microarrays, and to evaluate the response of the GARD model in predicting the efficacy of neoadjuvant radiotherapy. Fresh-frozen primary tumor from 64 patients with locally advanced rectal cancer undergoing neoadjuvant radiotherapy from 2015 to 2018 were included. The gene expression profile was analyzed using Affymetrix 3000Dx gene-chip scanner. The radiosensitivity index (RSI) and GARD were calculated using the pGRT™ algorithm. Neoadjuvant rectal cancer score (NAR) was selected as efficacy evaluation indicators. Patients were divided into high and low NAR scoring groups, and two-sample t-test was used to analyze the differences in GARD values between different NAR subgroups. ROC curves were used to calculate the cut-off values and the area under the curve (AUC) for assessing the validity of the GARD models. The personalized radiation dose ( pGRT dose )can be computed using the formula nd = GARD / (α + βd). Among patients, 1.5% T2, 46.3% T3, and 52.2% T4. Wherein pCR (n = 10; 15.6%) and no pCR (n = 54; 84.4%). The median NAR is 8.43 (rang from 0 to 50.34, IQR 3.75-14.98). NAR > 8.43 (n = 27; 42.2%) and NAR ≤ 8.43 (n = 37; 57.8%), suggesting that there are significant individual differences in clinical efficacy of patients with similar tumor stages and under the same treatment conditions. The median RSI is 0.48 (rang from 0.22 to 0.92, IQR 0.41-0.55). Median GARD was 18.40 rang from (rang from 2.26 to 37.52, IQR 14.94-22.28) within tumor tissue, suggesting individual differences in the efficacy of radiation therapy. The RSI value was significantly lower in the NAR low group (NAR ≤ 8.43) than in NAR high group (NAR > 8.43) (0.44 vs. 0.54, p = 0.0003). The GARD value was significantly higher in the NAR low group (NAR ≤ 8.43) than in NAR high group (NAR > 8.43) (21.01 vs. 15.88, p = 0.0004). Using the Receiver Operating Characteristic (ROC) curve analysis, a GARD threshold of 17 was identified as optimal, covering 37.5% of the 64-patient sample, with an area under the curve (AUC) of 0.75. In the external validation cohort, the high GARD score group demonstrated superior DFS compared to the low GARD score group(p < 0.001). Only 17% of patients had pGRT dose within the guideline recommended dose (45-50 Gy). The differences in NAR values among LARC patients receiving standard neoadjuvant radiotherapy suggest significant individual differences in clinical outcomes among patients with similar tumor stage and the same treatment conditions. Patients with a GARD value exceeding 17 exhibit a more favorable prognosis. Our results suggest that the gene expression-based pGRT™ algorithm has good efficacy prediction performance in preoperative concurrent radiotherapy for locally advanced rectal cancer, suggesting the potential clinical application of this method to guide the designation of individualized radiotherapy doses.
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Affiliation(s)
- Huang Xia
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies), Fuzhou, Fujian Province, People's Republic of China
| | - Zeyuan Li
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies), Fuzhou, Fujian Province, People's Republic of China
| | - Yineng Lin
- The Second Hospital of Zhangzhou, Zhangzhou, Fujian Province, People's Republic of China
| | - Yu Lin
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China
| | - Lijing Zeng
- Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China
| | - Benhua Xu
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China.
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies), Fuzhou, Fujian Province, People's Republic of China.
| | - Qiwei Yao
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian Province, People's Republic of China.
| | - Rong Zheng
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China.
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies), Fuzhou, Fujian Province, People's Republic of China.
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9
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Jin T, Ji J, Xu X, Li X, Gong B. Identification and validation of a novel 17 coagulation-related genes signature for predicting prognostic risk in colorectal cancer. Heliyon 2024; 10:e32687. [PMID: 38988584 PMCID: PMC11233961 DOI: 10.1016/j.heliyon.2024.e32687] [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: 04/13/2023] [Revised: 05/31/2024] [Accepted: 06/06/2024] [Indexed: 07/12/2024] Open
Abstract
Background Patients with colorectal cancer commonly experience disturbances in coagulation homeostasis. Activation of the coagulation system contributes to cancer-associated thrombosis as the second risk factor for death in cancer patients. This study intended to discover coagulation-related genes and construct a risk model for colorectal cancer patients' prognosis. Methods Coagulation-related genes were identified by searching coagulation-related pathways in the Molecular Signatures Database. Transcriptomic data and clinical data were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus datasets. Univariate Cox and backward stepwise regression were utilized to identify prognosis-related genes and construct a predictive risk model for the training cohort. Next, survival analysis determines the risk model's predictive power, correlation with clinicopathological characteristics, and nomogram. Additionally, we characterized the variances in immune cell infiltration, somatic mutations, immune checkpoint molecules, biological functions, and drug sensitivity between the high- and low-score patients. Result Eight hundred forty-five genes were obtained by searching the theme term "coagulation" after de-duplication. After univariate regression analysis, 69 genes correlated with prognosis were obtained from the Cancer Genome Atlas dataset. A signature consisting of 17 coagulation-related genes was established through backward stepwise regression. The Kaplan-Meier curve indicated a worse prognosis for high-score patients. Time-dependent receiver operating characteristic curve analysis demonstrated high accuracy in predicting overall survival. Further, the results were validated by two independent datasets (GSE39582 and GSE17536). Combined with clinicopathological characteristics, the risk model was proven to be an independent prognostic factor to predict poor pathological status and worse prognosis. Furthermore, high-score patients had significantly higher stromal cell infiltration. Low-score patients were associated with high infiltration of resting memory CD4+ T cells, activated CD4+ T cells, and T follicular helper cells. The low-score patients exhibited increased expression of immune checkpoint genes, and this might be relevant to their better prognosis. High-score patients exhibited lower IC50 values of Paclitaxel, Rapamycin, Temozolomide, Cyclophosphamide, etc. The differential signaling pathways mainly involve the calcium signaling pathway and the neuroactive ligand-receptor interaction. Lastly, a nomogram was constructed and showed a good prediction. Conclusion The prognostic signature of 17 coagulation-related genes had significant prognostic value for colorectal cancer patients. We expect to improve treatment modalities and benefit more patients through research on molecular features.
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Affiliation(s)
- Taojun Jin
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jianmei Ji
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaowen Xu
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xinxing Li
- Department of Gastrointestinal Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Biao Gong
- Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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10
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Mouillet-Richard S, Cazelles A, Sroussi M, Gallois C, Taieb J, Laurent-Puig P. Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine. Clin Cancer Res 2024; 30:2351-2358. [PMID: 38564259 PMCID: PMC11145159 DOI: 10.1158/1078-0432.ccr-23-3964] [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: 12/18/2023] [Revised: 01/31/2024] [Accepted: 03/13/2024] [Indexed: 04/04/2024]
Abstract
Over the past decade, our understanding of the diversity of colorectal cancer has expanded significantly, raising hopes of tailoring treatments more precisely for individual patients. A key achievement in this direction was the establishment of the consensus molecular classification, particularly identifying the challenging consensus molecular subtype (CMS) CMS4 associated with poor prognosis. Because of its aggressive nature, extensive research is dedicated to the CMS4 subgroup. Recent years have unveiled molecular and microenvironmental features at the tissue level specific to CMS4 colorectal cancer. This has paved the way for mechanistic studies and the development of preclinical models. Simultaneously, efforts have been made to easily identify patients with CMS4 colorectal cancer. Reassessing clinical trial results through the CMS classification lens has improved our understanding of the therapeutic challenges linked to this subtype. Exploration of the biology of CMS4 colorectal cancer is yielding potential biomarkers and novel treatment approaches. This overview aims to provide insights into the clinico-biological characteristics of the CMS4 subgroup, the molecular pathways driving this subtype, and available diagnostic options. We also emphasize the therapeutic challenges associated with this subtype, offering potential explanations. Finally, we summarize the current tailored treatments for CMS4 colorectal cancer emerging from fundamental and preclinical studies.
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Affiliation(s)
- Sophie Mouillet-Richard
- Team “Personalized medicine, pharmacogenomics, therapeutic optimization”, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Antoine Cazelles
- Team “Personalized medicine, pharmacogenomics, therapeutic optimization”, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Marine Sroussi
- Team “Personalized medicine, pharmacogenomics, therapeutic optimization”, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Claire Gallois
- Team “Personalized medicine, pharmacogenomics, therapeutic optimization”, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, APHP, Gastroenterology and Gastrointestinal Oncology Department, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, Paris, France
| | - Julien Taieb
- Team “Personalized medicine, pharmacogenomics, therapeutic optimization”, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, APHP, Gastroenterology and Gastrointestinal Oncology Department, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, Paris, France
| | - Pierre Laurent-Puig
- Team “Personalized medicine, pharmacogenomics, therapeutic optimization”, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, APHP, Department of Biology, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, Paris, France
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11
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Sanvicente García A, Pedregal M, Paniagua-Herranz L, Díaz-Tejeiro C, Nieto-Jiménez C, Pérez Segura P, Munkácsy G, Győrffy B, Calvo E, Moreno V, Ocaña A. Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D. Int J Mol Sci 2024; 25:5345. [PMID: 38791382 PMCID: PMC11121234 DOI: 10.3390/ijms25105345] [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: 04/09/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.
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Affiliation(s)
- Adrián Sanvicente García
- Experimental Therapeutics in Cancer Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (A.S.G.); (L.P.-H.); (C.D.-T.); (C.N.-J.)
- Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Manuel Pedregal
- START Madrid-Fundación Jiménez Díaz (FJD) Early Phase Program, Fundación Jiménez Díaz Hospital, 28040 Madrid, Spain; (M.P.); (E.C.); (V.M.)
| | - Lucía Paniagua-Herranz
- Experimental Therapeutics in Cancer Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (A.S.G.); (L.P.-H.); (C.D.-T.); (C.N.-J.)
| | - Cristina Díaz-Tejeiro
- Experimental Therapeutics in Cancer Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (A.S.G.); (L.P.-H.); (C.D.-T.); (C.N.-J.)
| | - Cristina Nieto-Jiménez
- Experimental Therapeutics in Cancer Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (A.S.G.); (L.P.-H.); (C.D.-T.); (C.N.-J.)
| | - Pedro Pérez Segura
- Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain;
| | - Gyöngyi Munkácsy
- Department of Bioinformatics, Semmelweis University, H-1094 Budapest, Hungary; (G.M.); (B.G.)
- Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, H-1094 Budapest, Hungary; (G.M.); (B.G.)
- Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- Research Centre for Natural Sciences, Institute of Enzymology, H-1117 Budapest, Hungary
- Department of Biophysics, Medical School, University of Pecs, H-7624 Pecs, Hungary
| | - Emiliano Calvo
- START Madrid-Fundación Jiménez Díaz (FJD) Early Phase Program, Fundación Jiménez Díaz Hospital, 28040 Madrid, Spain; (M.P.); (E.C.); (V.M.)
- START Madrid-HM Centro Integral Oncológico Clara Campal (CIOCC), Early Phase Program, HM Sanchinarro University Hospital, 28050 Madrid, Spain
| | - Víctor Moreno
- START Madrid-Fundación Jiménez Díaz (FJD) Early Phase Program, Fundación Jiménez Díaz Hospital, 28040 Madrid, Spain; (M.P.); (E.C.); (V.M.)
| | - Alberto Ocaña
- Experimental Therapeutics in Cancer Unit, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; (A.S.G.); (L.P.-H.); (C.D.-T.); (C.N.-J.)
- START Madrid-Fundación Jiménez Díaz (FJD) Early Phase Program, Fundación Jiménez Díaz Hospital, 28040 Madrid, Spain; (M.P.); (E.C.); (V.M.)
- Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain;
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
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12
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Kisakol B, Matveeva A, Salvucci M, Kel A, McDonough E, Ginty F, Longley DB, Prehn JHM. Identification of unique rectal cancer-specific subtypes. Br J Cancer 2024; 130:1809-1818. [PMID: 38532103 PMCID: PMC11130168 DOI: 10.1038/s41416-024-02656-0] [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: 11/03/2023] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Existing colorectal cancer subtyping methods were generated without much consideration of potential differences in expression profiles between colon and rectal tissues. Moreover, locally advanced rectal cancers at resection often have received neoadjuvant chemoradiotherapy which likely has a significant impact on gene expression. METHODS We collected mRNA expression profiles for rectal and colon cancer samples (n = 2121). We observed that (i) Consensus Molecular Subtyping (CMS) had a different prognosis in treatment-naïve rectal vs. colon cancers, and (ii) that neoadjuvant chemoradiotherapy exposure produced a strong shift in CMS subtypes in rectal cancers. We therefore clustered 182 untreated rectal cancers to find rectal cancer-specific subtypes (RSSs). RESULTS We identified three robust subtypes. We observed that RSS1 had better, and RSS2 had worse disease-free survival. RSS1 showed high expression of MYC target genes and low activity of angiogenesis genes. RSS2 exhibited low regulatory T cell abundance, strong EMT and angiogenesis signalling, and high activation of TGF-β, NF-κB, and TNF-α signalling. RSS3 was characterised by the deactivation of EGFR, MAPK and WNT pathways. CONCLUSIONS We conclude that RSS subtyping allows for more accurate prognosis predictions in rectal cancers than CMS subtyping and provides new insight into targetable disease pathways within these subtypes.
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Affiliation(s)
- Batuhan Kisakol
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, 2, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, 2, Ireland
| | - Anna Matveeva
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, 2, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, 2, Ireland
| | - Manuela Salvucci
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, 2, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, 2, Ireland
| | | | | | | | - Daniel B Longley
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, 2, Ireland.
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, 2, Ireland.
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13
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Jakab A, Patai ÁV, Darvas M, Tormássi-Bély K, Micsik T. Microenvironment, systemic inflammatory response and tumor markers considering consensus molecular subtypes of colorectal cancer. Pathol Oncol Res 2024; 30:1611574. [PMID: 38645565 PMCID: PMC11026638 DOI: 10.3389/pore.2024.1611574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 03/12/2024] [Indexed: 04/23/2024]
Abstract
Introduction: Colorectal carcinomas (CRC) are one of the most frequent malignancies worldwide. Based on gene expression profile analysis, CRCs can be classified into four distinct subtypes also known as the consensus molecular subtypes (CMS), which predict biological behaviour. Besides CMS, several other aspects of tumor microenvironment (TME) and systemic inflammatory response (SIR) influence the outcome of CRC patients. TME and inflammation have important role in the immune (CMS1) and mesenchymal (CMS4) subtypes, however, the relationship between these and systemic inflammation has not been assessed yet. Our objective was to evaluate the connection between CMS, TME and SIR, and to analyze the correlation between these markers and routinely used tumor markers, such as CEA (Carcinoembryonic Antigen) and CA19-9 (Carbohydrate Antigen 19-9). Methods: FFPE (Formalin Fixed Paraffin Embedded) samples of 185 CRC patients were collected. TME was described using tumor-stroma ratio (TSR), Klintrup-Makinen (KM) grade, and Glasgow Microenvironment Score (GMS). CMS classification was performed on tissue microarray using MLH1, PMS2, MSH2 and MSH6, and pan-cytokeratin, CDX2, FRMD6, HTR2B and ZEB1 immunohistochemical stains. Pre-operative tumor marker levels and inflammatory markers [C-reactive protein - CRP, albumin, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute platelet count (APC)] and patient history were retrieved using MedSolution database. Results: Amongst TME-markers, TSR correlated most consistently with adverse clinicopathological features (p < 0.001) and overall survival (p < 0.001). Elevated CRP and modified Glasgow Prognostic Score (mGPS) were associated with worse outcome and aggressive phenotype, similarly to tumor markers CEA and CA19-9. Stroma-Tumor Marker score (STM score), a new combined score of CA19-9 and TSR delivered the second best prognostication after mGPS. Furthermore, CMS4 showed association with TSR and several laboratory markers (albumin and platelet derived factors), but not with other SIR descriptors. CMS did not show any association with CEA and CA19-9 tumor markers. Conclusion: More routinely available TME, SIR and tumor markers alone and in combination deliver reliable prognostic data for choosing the patients with higher risk for propagation. CMS4 is linked with high TSR and poor prognosis, but in overall, CMS-classification showed only limited effect on SIR- and tumor-markers.
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Affiliation(s)
- Anna Jakab
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
| | - Árpád V. Patai
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Mónika Darvas
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Karolina Tormássi-Bély
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
| | - Tamás Micsik
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
- Saint George University Teaching Hospital of Fejér County, Székesfehérvár, Hungary
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14
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Lenz HJ, Parikh A, Spigel DR, Cohn AL, Yoshino T, Kochenderfer M, Elez E, Shao SH, Deming D, Holdridge R, Larson T, Chen E, Mahipal A, Ucar A, Cullen D, Baskin-Bey E, Kang T, Hammell AB, Yao J, Tabernero J. Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial. J Immunother Cancer 2024; 12:e008409. [PMID: 38485190 PMCID: PMC10941175 DOI: 10.1136/jitc-2023-008409] [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] [Accepted: 02/28/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8). METHODS CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed. RESULTS From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified. CONCLUSIONS The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted. TRIAL REGISTRATION NUMBER NCT03414983.
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Affiliation(s)
- Heinz-Josef Lenz
- Department of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Aparna Parikh
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David R Spigel
- Department of Oncology, Sarah Cannon Research Institute, Nashville, Tennessee, USA
| | - Allen L Cohn
- Department of Medical Oncology, US Oncology Research, Rocky Mountain Cancer Centers, Denver, Colorado, USA
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
| | | | - Elena Elez
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Dustin Deming
- Departments of Medicine and Oncology, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Regan Holdridge
- Comprehensive Cancer Centers of Nevada, Henderson, Nevada, USA
| | - Timothy Larson
- Department of Medical Oncology, Minnesota Oncology Hematology, Minneapolis, Minnesota, USA
| | - Eric Chen
- Department of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Antonio Ucar
- Miami Cancer Institute (part of Baptist Health South Florida), Miami, Florida, USA
| | - Dana Cullen
- Oncology Clinical Science, Bristol Myers Squibb, Princeton, New Jersey, USA
| | | | - Tong Kang
- Biostatistics, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Amy B Hammell
- Precision Medicine, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Jin Yao
- Translational Bioinformatics, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Josep Tabernero
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
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15
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Kreis J, Aybey B, Geist F, Brors B, Staub E. Stromal Signals Dominate Gene Expression Signature Scores That Aim to Describe Cancer Cell-intrinsic Stemness or Mesenchymality Characteristics. CANCER RESEARCH COMMUNICATIONS 2024; 4:516-529. [PMID: 38349551 PMCID: PMC10885853 DOI: 10.1158/2767-9764.crc-23-0383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 12/14/2023] [Accepted: 02/09/2024] [Indexed: 02/24/2024]
Abstract
Epithelial-to-mesenchymal transition (EMT) in cancer cells confers migratory abilities, a crucial aspect in the metastasis of tumors that frequently leads to death. In multiple studies, authors proposed gene expression signatures for EMT, stemness, or mesenchymality of tumors based on bulk tumor expression profiling. However, recent studies suggested that noncancerous cells from the microenvironment or macroenvironment heavily influence such signature profiles. Here, we strengthen these findings by investigating 11 published and frequently referenced gene expression signatures that were proposed to describe EMT-related (EMT, mesenchymal, or stemness) characteristics in various cancer types. By analyses of bulk, single-cell, and pseudobulk expression data, we show that the cell type composition of a tumor sample frequently dominates scores of these EMT-related signatures. A comprehensive, integrated analysis of bulk RNA sequencing (RNA-seq) and single-cell RNA-seq data shows that stromal cells, most often fibroblasts, are the main drivers of EMT-related signature scores. We call attention to the risk of false conclusions about tumor properties when interpreting EMT-related signatures, especially in a clinical setting: high patient scores of EMT-related signatures or calls of "stemness subtypes" often result from low cancer cell content in tumor biopsies rather than cancer cell-specific stemness or mesenchymal/EMT characteristics. SIGNIFICANCE Cancer self-renewal and migratory abilities are often characterized via gene module expression profiles, also called EMT or stemness gene expression signatures. Using published clinical tumor samples, cancer cell lines, and single cancer cells, we highlight the dominating influence of noncancer cells in low cancer cell content biopsies on their scores. We caution on their application for low cancer cell content clinical cancer samples with the intent to assign such characteristics or subtypes.
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Affiliation(s)
- Julian Kreis
- The healthcare business of Merck KGaA, Darmstadt, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Bogac Aybey
- The healthcare business of Merck KGaA, Darmstadt, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Felix Geist
- The healthcare business of Merck KGaA, Darmstadt, Germany
| | - Benedikt Brors
- Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg University, Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg University, Heidelberg, Germany
- Medical Faculty Heidelberg and Faculty of Biosciences, Heidelberg University, and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Eike Staub
- The healthcare business of Merck KGaA, Darmstadt, Germany
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Valdeolivas A, Amberg B, Giroud N, Richardson M, Gálvez EJC, Badillo S, Julien-Laferrière A, Túrós D, Voith von Voithenberg L, Wells I, Pesti B, Lo AA, Yángüez E, Das Thakur M, Bscheider M, Sultan M, Kumpesa N, Jacobsen B, Bergauer T, Saez-Rodriguez J, Rottenberg S, Schwalie PC, Hahn K. Profiling the heterogeneity of colorectal cancer consensus molecular subtypes using spatial transcriptomics. NPJ Precis Oncol 2024; 8:10. [PMID: 38200223 PMCID: PMC10781769 DOI: 10.1038/s41698-023-00488-4] [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: 02/24/2023] [Accepted: 12/04/2023] [Indexed: 01/12/2024] Open
Abstract
The consensus molecular subtypes (CMS) of colorectal cancer (CRC) is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signals, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our study illustrates the potential of ST to resolve CRC molecular heterogeneity and thereby help advance personalized therapy.
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Affiliation(s)
- Alberto Valdeolivas
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
| | - Bettina Amberg
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Nicolas Giroud
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Marion Richardson
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Eric J C Gálvez
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Solveig Badillo
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Alice Julien-Laferrière
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Demeter Túrós
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | | | - Isabelle Wells
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Benedek Pesti
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Amy A Lo
- Genentech, Inc, San Francisco, CA, USA
| | - Emilio Yángüez
- Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | | | - Michael Bscheider
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Marc Sultan
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Nadine Kumpesa
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Björn Jacobsen
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Tobias Bergauer
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Julio Saez-Rodriguez
- Faculty of Medicine and Heidelberg University Hospital, Institute of Computational Biomedicine, Heidelberg University, Heidelberg, Germany
| | - Sven Rottenberg
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Bern Center for Precision Medicine (BCPM), University of Bern, Bern, Switzerland
| | - Petra C Schwalie
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Kerstin Hahn
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
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17
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Papavassiliou KA, Delle Cave D, Papavassiliou AG. Targeting the TGF-β Signaling Axis in Metastatic Colorectal Cancer: Where Do We Stand? Int J Mol Sci 2023; 24:17101. [PMID: 38069421 PMCID: PMC10706985 DOI: 10.3390/ijms242317101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 12/01/2023] [Indexed: 12/18/2023] Open
Abstract
Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide [...].
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Affiliation(s)
- Kostas A Papavassiliou
- First University Department of Respiratory Medicine, 'Sotiria' Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Donatella Delle Cave
- Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', CNR, 80131 Naples, Italy
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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18
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Hirose Y, Taniguchi K. Intratumoral metabolic heterogeneity of colorectal cancer. Am J Physiol Cell Physiol 2023; 325:C1073-C1084. [PMID: 37661922 DOI: 10.1152/ajpcell.00139.2021] [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: 04/05/2021] [Revised: 07/31/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023]
Abstract
Although the metabolic phenotype within tumors is known to differ significantly from that of the surrounding normal tissue, the importance of this heterogeneity is just becoming widely recognized. Colorectal cancer (CRC) is often classified as the Warburg phenotype, a metabolic type in which the glycolytic system is predominant over oxidative phosphorylation (OXPHOS) in mitochondria for energy production. However, this dichotomy (glycolysis vs. OXPHOS) may be too simplistic and not accurately represent the metabolic characteristics of CRC. Therefore, in this review, we decompose metabolic phenomena into factors based on their source/origin and reclassify them into two categories: extrinsic and intrinsic. In the CRC context, extrinsic factors include those based on the environment, such as hypoxia, nutrient deprivation, and the tumor microenvironment, whereas intrinsic factors include those based on subpopulations, such as pathological subtypes and cancer stem cells. These factors form multiple layers inside and outside the tumor, affecting them additively, dominantly, or mutually exclusively. Consequently, the metabolic phenotype is a heterogeneous and fluid phenomenon reflecting the spatial distribution and temporal continuity of these factors. This allowed us to redefine the characteristics of specific metabolism-related factors in CRC and summarize and update our accumulated knowledge of their heterogeneity. Furthermore, we positioned tumor budding in CRC as an intrinsic factor and a novel form of metabolic heterogeneity, and predicted its metabolic dynamics, noting its similarity to circulating tumor cells and epithelial-mesenchymal transition. Finally, the possibilities and limitations of using human tumor tissue as research material to investigate and assess metabolic heterogeneity are discussed.
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Affiliation(s)
- Yoshinobu Hirose
- Department of Pathology, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Kohei Taniguchi
- Division of Translational Research, Center for Medical Research & Development, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
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19
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Ohnmacht AJ, Stahler A, Stintzing S, Modest DP, Holch JW, Westphalen CB, Hölzel L, Schübel MK, Galhoz A, Farnoud A, Ud-Dean M, Vehling-Kaiser U, Decker T, Moehler M, Heinig M, Heinemann V, Menden MP. The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer. Nat Commun 2023; 14:5391. [PMID: 37666855 PMCID: PMC10477267 DOI: 10.1038/s41467-023-41011-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/17/2023] [Indexed: 09/06/2023] Open
Abstract
Precision medicine has revolutionised cancer treatments; however, actionable biomarkers remain scarce. To address this, we develop the Oncology Biomarker Discovery (OncoBird) framework for analysing the molecular and biomarker landscape of randomised controlled clinical trials. OncoBird identifies biomarkers based on single genes or mutually exclusive genetic alterations in isolation or in the context of tumour subtypes, and finally, assesses predictive components by their treatment interactions. Here, we utilise the open-label, randomised phase III trial (FIRE-3, AIO KRK-0306) in metastatic colorectal carcinoma patients, who received either cetuximab or bevacizumab in combination with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI). We systematically identify five biomarkers with predictive components, e.g., patients with tumours that carry chr20q amplifications or lack mutually exclusive ERK signalling mutations benefited from cetuximab compared to bevacizumab. In summary, OncoBird characterises the molecular landscape and outlines actionable biomarkers, which generalises to any molecularly characterised randomised controlled trial.
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Affiliation(s)
- Alexander J Ohnmacht
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany
| | - Arndt Stahler
- Charité Universitätsmedizin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117, Berlin, Germany
| | - Sebastian Stintzing
- Charité Universitätsmedizin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117, Berlin, Germany
- German Cancer Consortium (DKTK), partner sites Berlin and Munich, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Dominik P Modest
- Charité Universitätsmedizin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117, Berlin, Germany
| | - Julian W Holch
- German Cancer Consortium (DKTK), partner sites Berlin and Munich, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Department of Medicine III and Comprehensive Cancer Center Munich, University Hospital, Ludwig-Maximilians University Munich, 81377, Munich, Germany
| | - C Benedikt Westphalen
- Department of Medicine III and Comprehensive Cancer Center Munich, University Hospital, Ludwig-Maximilians University Munich, 81377, Munich, Germany
| | - Linus Hölzel
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
| | - Marisa K Schübel
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany
| | - Ana Galhoz
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany
| | - Ali Farnoud
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
| | - Minhaz Ud-Dean
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
| | | | | | - Markus Moehler
- Department of Medicine I and Research Center for Immunotherapy (FZI), Johannes Gutenberg-University Clinic, 55131, Mainz, Germany
| | - Matthias Heinig
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
| | - Volker Heinemann
- Department of Medicine III and Comprehensive Cancer Center Munich, University Hospital, Ludwig-Maximilians University Munich, 81377, Munich, Germany.
| | - Michael P Menden
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany.
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany.
- Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, 3010, Australia.
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20
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Offermans K, Jenniskens JCA, Simons CCJM, Samarska I, Fazzi GE, Smits KM, Schouten LJ, Weijenberg MP, Grabsch HI, van den Brandt PA. Association between adjuvant therapy and survival in colorectal cancer patients according to metabolic Warburg-subtypes. J Cancer Res Clin Oncol 2023; 149:6271-6282. [PMID: 36723668 PMCID: PMC10356897 DOI: 10.1007/s00432-023-04581-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: 12/09/2022] [Accepted: 01/08/2023] [Indexed: 02/02/2023]
Abstract
PURPOSE Tumor location and tumor node metastasis (TNM) stage guide treatment decisions in colorectal cancer (CRC) patients. However, patients with the same disease stage do not benefit equally from adjuvant therapy. Hence, there remains an urgent clinical need to identify prognostic and/or predictive biomarker(s) to personalize treatment decisions. In this exploratory study, we investigated whether our previously defined metabolic Warburg-subtypes can predict which CRC patients might derive survival benefit from adjuvant therapy. METHODS Information regarding treatment (surgery only: n = 1451; adjuvant radiotherapy: n = 82; or adjuvant chemotherapy: n = 260) and Warburg-subtype (Warburg-low: n = 485, -moderate: n = 641, or -high: n = 667) was available for 1793 CRC patients from the Netherlands Cohort Study (NLCS). Kaplan-Meier curves and Cox regression models were used to investigate survival benefit from adjuvant therapy compared to surgery-only for the different Warburg-subtypes. RESULTS Patients with Warburg-moderate CRC (HRCRC-specific 0.64; 95% CI 0.47-0.86, HRoverall 0.61; 95% CI 0.47-0.80), and possibly Warburg-high CRC (HRCRC-specific 0.86; 95% CI 0.65-1.14, HRoverall 0.82; 95% CI 0.64-1.05), had survival benefit from adjuvant therapy. No survival benefit was observed for patients with Warburg-low CRC (HRCRC-specific 1.07; 95% CI 0.76-1.52, HRoverall 0.95; 95% CI 0.70-1.30). There was a significant interaction between Warburg-subtype and adjuvant therapy for CRC-specific survival (p = 0.049) and overall survival (p = 0.035). CONCLUSION Our results suggest that Warburg-subtypes may predict survival benefit from adjuvant therapy in CRC patients. A survival benefit from adjuvant therapy was observed for patients with Warburg-moderate and possibly Warburg-high CRC, but not for patients with Warburg-low CRC. Future prospective studies are necessary to validate our findings.
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Affiliation(s)
- Kelly Offermans
- Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Josien C A Jenniskens
- Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Colinda C J M Simons
- Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Iryna Samarska
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Gregorio E Fazzi
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Kim M Smits
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Leo J Schouten
- Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
| | - Piet A van den Brandt
- Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
- Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center+, Maastricht, The Netherlands.
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21
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Harmon C, Zaborowski A, Moore H, St Louis P, Slattery K, Duquette D, Scanlan J, Kane H, Kunkemoeller B, McIntyre CL, Scannail AN, Moran B, Anderson AC, Winter D, Brennan D, Brehm MA, Lynch L. γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors. NATURE CANCER 2023; 4:1122-1137. [PMID: 37474835 DOI: 10.1038/s43018-023-00589-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 06/05/2023] [Indexed: 07/22/2023]
Abstract
γδ T cells are important tissue-resident, innate T cells that are critical for tissue homeostasis. γδ cells are associated with positive prognosis in most tumors; however, little is known about their heterogeneity in human cancers. Here, we phenotyped innate and adaptive cells in human colorectal (CRC) and endometrial cancer. We found striking differences in γδ subsets and function in tumors compared to normal tissue, and in the γδ subsets present in tumor types. In CRC, an amphiregulin (AREG)-producing subset emerges, while endometrial cancer is infiltrated by cytotoxic cells. In humanized CRC models, tumors induced this AREG phenotype in Vδ1 cells after adoptive transfer. To exploit the beneficial roles of γδ cells for cell therapy, we developed an expansion method that enhanced cytotoxic function and boosted metabolic flexibility, while eliminating AREG production, achieving greater tumor infiltration and tumor clearance. This method has broad applications in cellular therapy as an 'off-the-shelf' treatment option.
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Affiliation(s)
- Cathal Harmon
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Alexandra Zaborowski
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Haim Moore
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Pamela St Louis
- Program in Molecular Medicine and the Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Karen Slattery
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Danielle Duquette
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - John Scanlan
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Harry Kane
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Britta Kunkemoeller
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Claire L McIntyre
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Aine Ni Scannail
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Bruce Moran
- Department of Pathology, St. Vincent's University Hospital, Dublin, Ireland
| | - Ana C Anderson
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA
| | - Des Winter
- Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
| | - Donal Brennan
- Gynecological Oncology Group, School of Medicine, University College Dublin, Dublin, Ireland
| | - Michael A Brehm
- Program in Molecular Medicine and the Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lydia Lynch
- Department of Endocrinology, Brigham & Women's Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
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22
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Kolisnik T, Sulit AK, Schmeier S, Frizelle F, Purcell R, Smith A, Silander O. Identifying important microbial and genomic biomarkers for differentiating right- versus left-sided colorectal cancer using random forest models. BMC Cancer 2023; 23:647. [PMID: 37434131 PMCID: PMC10337110 DOI: 10.1186/s12885-023-10848-9] [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: 10/30/2022] [Accepted: 04/13/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a heterogeneous disease, with subtypes that have different clinical behaviours and subsequent prognoses. There is a growing body of evidence suggesting that right-sided colorectal cancer (RCC) and left-sided colorectal cancer (LCC) also differ in treatment success and patient outcomes. Biomarkers that differentiate between RCC and LCC are not well-established. Here, we apply random forest (RF) machine learning methods to identify genomic or microbial biomarkers that differentiate RCC and LCC. METHODS RNA-seq expression data for 58,677 coding and non-coding human genes and count data for 28,557 human unmapped reads were obtained from 308 patient CRC tumour samples. We created three RF models for datasets of human genes-only, microbes-only, and genes-and-microbes combined. We used a permutation test to identify features of significant importance. Finally, we used differential expression (DE) and paired Wilcoxon-rank sum tests to associate features with a particular side. RESULTS RF model accuracy scores were 90%, 70%, and 87% with area under curve (AUC) of 0.9, 0.76, and 0.89 for the human genomic, microbial, and combined feature sets, respectively. 15 features were identified as significant in the model of genes-only, 54 microbes in the model of microbes-only, and 28 genes and 18 microbes in the model with genes-and-microbes combined. PRAC1 expression was the most important feature for differentiating RCC and LCC in the genes-only model, with HOXB13, SPAG16, HOXC4, and RNLS also playing a role. Ruminococcus gnavus and Clostridium acetireducens were the most important in the microbial-only model. MYOM3, HOXC4, Coprococcus eutactus, PRAC1, lncRNA AC012531.25, Ruminococcus gnavus, RNLS, HOXC6, SPAG16 and Fusobacterium nucleatum were most important in the combined model. CONCLUSIONS Many of the identified genes and microbes among all models have previously established associations with CRC. However, the ability of RF models to account for inter-feature relationships within the underlying decision trees may yield a more sensitive and biologically interconnected set of genomic and microbial biomarkers.
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Affiliation(s)
- Tyler Kolisnik
- School of Natural Sciences, Massey University, Auckland, New Zealand.
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
| | - Arielle Kae Sulit
- School of Natural Sciences, Massey University, Auckland, New Zealand
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | | | - Frank Frizelle
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Rachel Purcell
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Adam Smith
- School of Mathematical and Computational Sciences, Massey University, Auckland, New Zealand
| | - Olin Silander
- School of Natural Sciences, Massey University, Auckland, New Zealand
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23
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Wong CC, Yu J. Colorectal Cancer Subtyping With Microbiome-A Game Changer for Personalized Medicine? Gastroenterology 2023; 165:25-27. [PMID: 37121332 DOI: 10.1053/j.gastro.2023.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/02/2023]
Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
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24
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Wen X, Ye X, Yang X, Jiang R, Qian C, Wang X. The crosstalk between intestinal bacterial microbiota and immune cells in colorectal cancer progression. Clin Transl Oncol 2023; 25:620-632. [PMID: 36376701 DOI: 10.1007/s12094-022-02995-5] [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: 07/18/2022] [Accepted: 10/26/2022] [Indexed: 11/16/2022]
Abstract
Different types of cells that are involved in tumor immunity play a significant part in antitumor therapy. The intestinal microbiota consist of the trillions of diverse microorganisms that inhabit the gastrointestinal tract. Recently, much emphasis has been paid to the link between these symbionts and colorectal cancer (CRC). This association might be anything from oncogenesis and cancer development to resistance or susceptibility to chemotherapeutic medicines. Cancer patients have a significantly different microbial composition in their guts compared to healthy persons. The microbiome may play a role in the development and development of cancer through the modulation of tumor immunosurveillance, as shown by these studies; however, the specific processes underlying this role are still poorly understood. This review focuses on the relationship between the intestinal bacterial microbiota and immune cells to determine how the commensal microbiome influences the initiation and development of CRC.
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Affiliation(s)
- Xiaozi Wen
- Linping Campus of the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xufang Ye
- Linping Campus of the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xuejun Yang
- Linping Campus of the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Rujin Jiang
- Linping Campus of the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chunyan Qian
- Linping Campus of the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xianjun Wang
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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25
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Zhu Q, Rao B, Chen Y, Jia P, Wang X, Zhang B, Wang L, Zhao W, Hu C, Tang M, Yu K, Chen W, Pan L, Xu Y, Luo H, Wang K, Li B, Shi H. In silico development and in vitro validation of a novel five-gene signature for prognostic prediction in colon cancer. Am J Cancer Res 2023; 13:45-65. [PMID: 36777511 PMCID: PMC9906087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 12/24/2022] [Indexed: 02/14/2023] Open
Abstract
Colon cancer is one of the most common cancers in digestive system, and its prognosis remains unsatisfactory. Therefore, this study aimed to identify gene signatures that could effectively predict the prognosis of colon cancer patients by examining the data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. LASSO-Cox regression analysis generated a five-gene signature (DCBLD2, RAB11FIP1, CTLA4, HOXC6 and KRT6A) that was associated with patient survival in the TCGA cohort. The prognostic value of this gene signature was further validated in two independent GEO datasets. GO enrichment revealed that the function of this gene signature was mainly associated with extracellular matrix organization, collagen-containing extracellular matrix, and extracellular matrix structural constituent. Moreover, a nomogram was established to facilitate the clinical application of this signature. The relationships among the gene signature, mutational landscape and immune infiltration cells were also investigated. Importantly, this gene signature also reliably predicted the overall survival in IMvigor210 anti-PD-L1 cohort. In addition to the bioinformatics study, we also conducted a series of in vitro experiments to demonstrate the effect of the signature genes on the proliferation, migration, and invasion of colon cancer cells. Collectively, our data demonstrated that this five-gene signature might serve as a promising prognostic biomarker and shed light on the development of personalized treatment in colon cancer patients.
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Affiliation(s)
- Qiankun Zhu
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Benqiang Rao
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Yongbing Chen
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Pingping Jia
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Xin Wang
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Bingdong Zhang
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Lin Wang
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Wanni Zhao
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Chunlei Hu
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Meng Tang
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Kaiying Yu
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
| | - Wei Chen
- Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China,Department of Intensive Care Unit, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China
| | - Lei Pan
- Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China,Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China
| | - Yu Xu
- Department of General Surgery, The First Affiliated Hospital of Kunming Medical UniversityKunming 650032, Yunnan, The People’s Republic of China
| | - Huayou Luo
- Department of General Surgery, The First Affiliated Hospital of Kunming Medical UniversityKunming 650032, Yunnan, The People’s Republic of China
| | - Kunhua Wang
- Yunnan UniversityKunming 650091, Yunnan, The People’s Republic of China
| | - Bo Li
- Department of General Surgery, The Affiliated Hospital of Yunnan UniversityKunming 650091, Yunnan, The People’s Republic of China
| | - Hanping Shi
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical UniversityBeijing 100038, The People’s Republic of China,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and NutritionBeijing 100038, The People’s Republic of China,Key Laboratory of Cancer FSMP for State Market RegulationBeijing 100038, The People’s Republic of China,Ninth School of Clinical Medicine, Peking UniversityBeijing 100038, The People’s Republic of China
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26
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Zhou Y, Shao Y, Hu W, Zhang J, Shi Y, Kong X, Jiang J. A novel long noncoding RNA SP100-AS1 induces radioresistance of colorectal cancer via sponging miR-622 and stabilizing ATG3. Cell Death Differ 2023; 30:111-124. [PMID: 35978049 PMCID: PMC9883267 DOI: 10.1038/s41418-022-01049-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/01/2023] Open
Abstract
Although radiotherapy is an essential modality in the treatment of colorectal cancer (CRC), the incidence of radioresistance remains high clinically. Long noncoding RNAs (lncRNAs) reportedly play critical roles in CRC radioresistance by regulating genes or proteins at the transcriptional or post-translational levels. This study aimed to identify novel lncRNAs involved in radioresistance. We found that SP100-AS1 (lncRNA targeting antisense sequence of SP100 gene) was upregulated in radioresistant CRC patient tissues using RNA-seq analysis. Importantly, knockdown of SP100-AS1 significantly reduced radioresistance, cell proliferation, and tumor formation in vitro and in vivo. Mechanistically, mass spectrometry and bioinformatics analyses were used to identify the interacting proteins and microRNAs of SP100-AS1, respectively. Moreover, SP100-AS1 was found to interact with and stabilize ATG3 protein through the ubiquitination-dependent proteasome pathway. In addition, it could serve as a sponge for miR-622, which targeted ATG3 mRNA and affected autophagic activity. Thus, lncRNA SP100-AS1 could act as a radioresistance factor in CRC patients via RNA sponging and protein stabilizing mechanisms. In conclusion, the present study indicates that SP100-AS1/miR-622/ATG3 axis contributes to radioresistance and autophagic activity in CRC patients, suggesting it has huge prospects as a therapeutic target for improving CRC response to radiation therapy.
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Affiliation(s)
- You Zhou
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou, 213003, China
| | - Yingjie Shao
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Jinping Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, 215123, China
| | - Xiangyin Kong
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jingting Jiang
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, China.
- Institute of Cell Therapy, Soochow University, Changzhou, 213003, China.
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27
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The In Vitro Adaptation of Patient-Derived Organoids Suggests Alternative Strategies against CMS1 Colorectal Cancer: When the Microenvironment Does Make the Difference. Cancers (Basel) 2022; 14:cancers14246086. [PMID: 36551571 PMCID: PMC9775687 DOI: 10.3390/cancers14246086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is a relatively slow-growing tumor that can be treated successfully when identified in the early stages [...].
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28
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Hou W, Yi C, Zhu H. Predictive biomarkers of colon cancer immunotherapy: Present and future. Front Immunol 2022; 13:1032314. [PMID: 36483562 PMCID: PMC9722772 DOI: 10.3389/fimmu.2022.1032314] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022] Open
Abstract
Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.
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Affiliation(s)
- Wanting Hou
- Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Cheng Yi
- Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Hong Zhu
- Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan, China
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29
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Molecular Subtypes Based on Cuproptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Colorectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:5034092. [PMID: 36276275 PMCID: PMC9579866 DOI: 10.1155/2022/5034092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/31/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022]
Abstract
Recent studies have demonstrated the biological significance of cuproptosis modification, a newly discovered programmed cell death, in tumor progression. Nonetheless, the potential role of cuproptosis-related genes (CRGs) in the immune landscape and tumor microenvironment (TME) formation of colorectal cancer (CRC) remains unknown. We comprehensively assessed cuproptosis modification patterns of 1339 CRC samples based on 27 CRGs and systematically analyzed the correlation of these patterns with TME. The CRG-score was constructed to quantify cuproptosis characteristics by LASSO and multivariate Cox regression methods, and its predictive capability was validated in an independent cohort. We identified three distinct cuproptosis modification patterns in CRC. The TME immune cell infiltration demonstrated immune heterogeneity among these three subtypes. Enrichment for multiple metabolism signatures was pronounced in cluster A. Cluster C was significantly correlated with the signaling pathways of immune activation-related, resulting in poor prognoses. Cluster B with mixed features possibly represents a transition phenotype or intratumoral heterogeneity. Then, based on constructed eight-gene CRG-score, we found that the signature could predict the disease-free survival of CRC patients, and the low CRG-score was related to increased neoantigen load, immunity activation, and microsatellite instability-high (MSI-H). Additionally, we observed significant correlations of the CRG-score with the cancer stem cell index and chemotherapeutic drug susceptibility. This study demonstrated that cuproptosis was correlated with tumor progression, prognosis, and TME. Our findings may improve the understanding of CRGs in TME infiltration characterization of CRC patients and contribute to guiding more effective clinical therapeutic strategies.
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30
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Maslankova J, Vecurkovska I, Rabajdova M, Katuchova J, Kicka M, Gayova M, Katuch V. Regulation of transforming growth factor-β signaling as a therapeutic approach to treating colorectal cancer. World J Gastroenterol 2022. [PMID: 36156927 DOI: 10.3748/wjg.v28.i33.4744.pmid:36156927;pmcid:pmc9476856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
According to data from 2020, Slovakia has long been among the top five countries with the highest incidence rate of colorectal cancer (CRC) worldwide, and the rate is continuing to rise every year. In approximately 80% of CRC cases, allelic loss (loss of heterozygosity, LOH) occurs in the long arm of chromosome 18q. The most important genes that can be silenced by 18q LOH or mutations are small mothers against decapentaplegic homolog (SMAD) 2 and SMAD4, which are intracellular mediators of transforming growth factor (TGF)-β superfamily signals. TGF-β plays an important role in the pro-oncogenic processes, including such properties as invasion, epithelial-mesenchymal transition (commonly known as EMT), promotion of angiogenesis, and immunomodulatory effects. Several recent studies have reported that activation of TGF-β signaling is related to drug resistance in CRC. Because the mechanisms of drug resistance are different between patients in different stages of CRC, personalized treatment is more effective. Therefore, knowledge of the activation and inhibition of factors that affect the TGF-β signaling pathway is very important.
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Affiliation(s)
- Jana Maslankova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice 04011, Slovakia
| | - Ivana Vecurkovska
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice 04011, Slovakia
| | - Miroslava Rabajdova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice 04011, Slovakia
| | - Jana Katuchova
- First Department of Surgery, Medical Faculty of Safarik University, Kosice 04011, Kosicky kraj, Slovakia.
| | - Milos Kicka
- First Department of Surgery, Medical Faculty of Safarik University, Kosice 04011, Kosicky kraj, Slovakia
| | - Michala Gayova
- Department of Burns and Reconstructive Surgery, Medical Faculty at Safarik University and University Hospital, Kosice 04011, Slovakia
| | - Vladimir Katuch
- Department of Neurosurgery, Medical Faculty at Safarik University and University Hospital, Kosice 04011, Slovakia
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31
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Maslankova J, Vecurkovska I, Rabajdova M, Katuchova J, Kicka M, Gayova M, Katuch V. Regulation of transforming growth factor-β signaling as a therapeutic approach to treating colorectal cancer. World J Gastroenterol 2022; 28:4744-4761. [PMID: 36156927 PMCID: PMC9476856 DOI: 10.3748/wjg.v28.i33.4744] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/06/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
According to data from 2020, Slovakia has long been among the top five countries with the highest incidence rate of colorectal cancer (CRC) worldwide, and the rate is continuing to rise every year. In approximately 80% of CRC cases, allelic loss (loss of heterozygosity, LOH) occurs in the long arm of chromosome 18q. The most important genes that can be silenced by 18q LOH or mutations are small mothers against decapentaplegic homolog (SMAD) 2 and SMAD4, which are intracellular mediators of transforming growth factor (TGF)-β superfamily signals. TGF-β plays an important role in the pro-oncogenic processes, including such properties as invasion, epithelial-mesenchymal transition (commonly known as EMT), promotion of angiogenesis, and immunomodulatory effects. Several recent studies have reported that activation of TGF-β signaling is related to drug resistance in CRC. Because the mechanisms of drug resistance are different between patients in different stages of CRC, personalized treatment is more effective. Therefore, knowledge of the activation and inhibition of factors that affect the TGF-β signaling pathway is very important.
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Affiliation(s)
- Jana Maslankova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice 04011, Slovakia
| | - Ivana Vecurkovska
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice 04011, Slovakia
| | - Miroslava Rabajdova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Kosice 04011, Slovakia
| | - Jana Katuchova
- First Department of Surgery, Medical Faculty of Safarik University, Kosice 04011, Kosicky kraj, Slovakia
| | - Milos Kicka
- First Department of Surgery, Medical Faculty of Safarik University, Kosice 04011, Kosicky kraj, Slovakia
| | - Michala Gayova
- Department of Burns and Reconstructive Surgery, Medical Faculty at Safarik University and University Hospital, Kosice 04011, Slovakia
| | - Vladimir Katuch
- Department of Neurosurgery, Medical Faculty at Safarik University and University Hospital, Kosice 04011, Slovakia
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32
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Qian Y, Itzel T, Ebert M, Teufel A. Deep View of HCC Gene Expression Signatures and Their Comparison with Other Cancers. Cancers (Basel) 2022; 14:cancers14174322. [PMID: 36077860 PMCID: PMC9454845 DOI: 10.3390/cancers14174322] [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: 07/15/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Gene expression signatures correlate genetic alterations with specific clinical features, providing the potential for clinical usage. A plethora of HCC-dependent gene signatures have been developed in the last two decades. However, none of them has made its way into clinical practice. Thus, we investigated the specificity of public gene signatures to HCC by establishing a comparative transcriptomic analysis, as this may be essential for clinical applications. METHODS We collected 10 public HCC gene signatures and evaluated them by utilizing four different (commercial and non-commercial) gene expression profile comparison tools: Oncomine Premium, SigCom LINCS, ProfileChaser (modified version), and GENEVA, which can assign similar pre-analyzed profiles of patients with tumors or cancer cell lines to our gene signatures of interests. Among the query results of each tool, different cancer entities were screened. In addition, seven breast and colorectal cancer gene signatures were included in order to further challenge tumor specificity of gene expression signatures. RESULTS Although the specificity of the evaluated HCC gene signatures varied considerably, none of the gene signatures showed strict specificity to HCC. All gene signatures exhibited potential significant specificity to other cancers, particularly for colorectal and breast cancer. Since signature specificity proved challenging, we furthermore investigated common core genes and overlapping enriched pathways among all gene signatures, which, however, showed no or only very little overlap, respectively. CONCLUSION Our study demonstrates that specificity, independent validation, and clinical use of HCC genetic signatures solely relying on gene expression remains challenging. Furthermore, our work made clear that standards in signature generation and statistical methods but potentially also in tissue preparation are urgently needed.
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Affiliation(s)
- Yuquan Qian
- Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Timo Itzel
- Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Matthias Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Andreas Teufel
- Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Correspondence: ; Tel.: +49-(0)621-383-4983; Fax: +49-(0)621-383-1467
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33
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Caspi A, Entezari AA, Crutcher M, Snook AE, Waldman SA. Guanylyl cyclase C as a diagnostic and therapeutic target in colorectal cancer. Per Med 2022; 19:457-472. [PMID: 35920071 DOI: 10.2217/pme-2022-0026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 06/16/2022] [Indexed: 11/21/2022]
Abstract
Colorectal cancer remains a major cause of mortality in the USA, despite advances in prevention and screening. Existing therapies focus primarily on generic treatment such as surgical intervention and chemotherapy, depending on disease severity. As personalized medicine and targeted molecular oncology continue to develop as promising treatment avenues, there has emerged a need for effective targets and biomarkers of colorectal cancer. The transmembrane receptor guanylyl cyclase C (GUCY2C) regulates intestinal homeostasis and has emerged as a tumor suppressor. Further, it is universally expressed in advanced metastatic colorectal tumors, as well as other cancer types that arise through intestinal metaplasia. In this context, GUCY2C satisfies many characteristics of a compelling target and biomarker for gastrointestinal malignancies.
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Affiliation(s)
- Adi Caspi
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Ariana A Entezari
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Madison Crutcher
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Adam E Snook
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Scott A Waldman
- Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
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34
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Wozniakova M, Skarda J, Raska M. The Role of Tumor Microenvironment and Immune Response in Colorectal Cancer Development and Prognosis. Pathol Oncol Res 2022; 28:1610502. [PMID: 35936516 PMCID: PMC9350736 DOI: 10.3389/pore.2022.1610502] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. The patient’s prognosis largely depends on the tumor stage at diagnosis. The pathological TNM Classification of Malignant Tumors (pTNM) staging of surgically resected cancers represents the main prognostic factor and guidance for decision-making in CRC patients. However, this approach alone is insufficient as a prognostic predictor because clinical outcomes in patients at the same histological tumor stage can still differ. Recently, significant progress in the treatment of CRC has been made due to improvements in both chemotherapy and surgical management. Immunotherapy-based approaches are one of the most rapidly developing areas of tumor therapy. This review summarizes the current knowledge about the tumor microenvironment (TME), immune response and its interactions with CRC development, immunotherapy and prognosis.
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Affiliation(s)
- Maria Wozniakova
- Institute of Pathology and Molecular Genetics, University Hospital Ostrava, Ostrava, Czechia
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
- *Correspondence: Maria Wozniakova,
| | - Jozef Skarda
- Institute of Pathology and Molecular Genetics, University Hospital Ostrava, Ostrava, Czechia
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia
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35
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Adam RS, Poel D, Ferreira Moreno L, Spronck JMA, de Back TR, Torang A, Gomez Barila PM, ten Hoorn S, Markowetz F, Wang X, Verheul HMW, Buffart TE, Vermeulen L. Development of a miRNA-based classifier for detection of colorectal cancer molecular subtypes. Mol Oncol 2022; 16:2693-2709. [PMID: 35298091 PMCID: PMC9297751 DOI: 10.1002/1878-0261.13210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 01/10/2022] [Accepted: 03/15/2022] [Indexed: 11/16/2022] Open
Abstract
Previously, colorectal cancer (CRC) has been classified into four distinct molecular subtypes based on transcriptome data. These consensus molecular subtypes (CMSs) have implications for our understanding of tumor heterogeneity and the prognosis of patients. So far, this classification has been based on the use of messenger RNAs (mRNAs), although microRNAs (miRNAs) have also been shown to play a role in tumor heterogeneity and biological differences between CMSs. In contrast to mRNAs, miRNAs have a smaller size and increased stability, facilitating their detection. Therefore, we built a miRNA-based CMS classifier by converting the existing mRNA-based CMS classification using machine learning (training dataset of n = 271). The performance of this miRNA-assigned CMS classifier (CMS-miRaCl) was evaluated in several datasets, achieving an overall accuracy of ~ 0.72 (0.6329-0.7987) in the largest dataset (n = 158). To gain insight into the biological relevance of CMS-miRaCl, we evaluated the most important features in the classifier. We found that miRNAs previously reported to be relevant in microsatellite-instable CRCs or Wnt signaling were important features for CMS-miRaCl. Following further studies to validate its robustness, this miRNA-based alternative might simplify the implementation of CMS classification in clinical workflows.
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Affiliation(s)
- Ronja S. Adam
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Dennis Poel
- Department of Medical OncologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Leandro Ferreira Moreno
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Joey M. A. Spronck
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Tim R. de Back
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Arezo Torang
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Patricia M. Gomez Barila
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Sanne ten Hoorn
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | | | - Xin Wang
- Department of Biomedical SciencesCity University of Hong KongKowloon TongHong Kong
- Shenzhen Research InstituteCity University of Hong KongShenzhenChina
| | - Henk M. W. Verheul
- Department of Medical OncologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Tineke E. Buffart
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Department of Gastrointestinal OncologyNetherlands Cancer InstituteAmsterdamThe Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology (LEXOR)Center for Experimental and Molecular Medicine (CEMM)Cancer Center Amsterdam and Amsterdam Gastroenterology and MetabolismAmsterdam University Medical CentersThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
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Hino H, Shiomi A, Hatakeyama K, Kagawa H, Manabe S, Yamaoka Y, Nagashima T, Ohshima K, Urakami K, Akiyama Y, Yamaguchi K. Comprehensive genetic characterization of rectal cancer in a large cohort of Japanese patients: differences according to tumor location. J Gastroenterol 2022; 57:476-485. [PMID: 35449312 DOI: 10.1007/s00535-022-01875-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 04/03/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND In clinical practice, rectal cancer (RC) is classified according to tumor location. However, RC's genetic characteristics according to tumor location remain unclear. Therefore, we aimed to compare RC's genetic characteristics according to tumor location. METHODS In 611 patients with surgically resected RC, we performed genetic analyses and compared the results between low and other RCs. Low RC was defined according to the European Society for Medical Oncology (ESMO) guidelines and Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma (JCCRC). RESULTS KRAS mutation accumulation was significantly higher in low RC under the ESMO classification. Gene expression levels significantly differed between the groups for CTNNB1, KRAS, and ERBB2, under the ESMO classification and for TP53, KRAS, and ERBB2 under the JCCRC. Under the JCCRC, low RC had a significantly higher prevalence of fusion genes, such as EIF3E-RSPO2, PTPRK-RSPO3, and VTI1A-TCF7L2. Consensus molecular subtype (CMS) distribution was significantly different between the groups under both classifications. In particular, low RC had lower and higher frequencies of CMS2 and CMS4, respectively. CMS2 and CMS4 frequencies in low RC were 14.8% and 41.5% under the ESMO classification and 14.5% and 41.6% under the JCCRC, respectively. Multivariate Cox regression analysis demonstrated that pT3-4, pN1-2, and CMS4 were associated with poor relapse-free survival. CONCLUSIONS Low RC exhibited distinct genetic characteristics from other RCs. In particular, CMS4 was more frequent in low RC and was a risk factor for poor prognosis. These findings potentially avail further information regarding tumor biology and could lead to improvements in RC treatment.
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Affiliation(s)
- Hitoshi Hino
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Keiichi Hatakeyama
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Hiroyasu Kagawa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Shoichi Manabe
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Yusuke Yamaoka
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Takeshi Nagashima
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan.,SRL Inc., Shinjuku-ku, Tokyo, 163-0409, Japan
| | - Keiichi Ohshima
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Yasuto Akiyama
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, 411-8777, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center, Sunto-gun, Shizuoka, 411-8777, Japan
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Dai Z, Peng X, Guo Y, Shen X, Ding W, Fu J, Liang Z, Song J. Metabolic pathway-based molecular subtyping of colon cancer reveals clinical immunotherapy potential and prognosis. J Cancer Res Clin Oncol 2022; 149:2393-2416. [PMID: 35731273 DOI: 10.1007/s00432-022-04070-6] [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: 05/11/2022] [Accepted: 05/11/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Colon cancer presents challenges to clinical diagnosis and management due to its high heterogeneity. For more efficient and convenient diagnosis and treatment of colon cancer, we are committed to characterizing the molecular features of colon cancer by pioneering a classification system based on metabolic pathways. METHODS Based on the 113 metabolic pathways and genes collected in the previous stage, we scored and filtered the metabolic pathways of each sample in the training set by ssGSEA, and obtained 16 metabolic pathways related to colon cancer recurrence. In consistent clustering of training set samples with recurrence-related metabolic pathway scores, we identified two robust molecular subtypes of colon cancer (MC1 and MC2). Furthermore, we performed multi-angle analysis on the survival differences of subtypes, metabolic characteristics, clinical characteristics, functional enrichment, immune infiltration, differences with other subtypes, stemness indices, TIDE prediction, and drug sensitivity, and finally constructed colon cancer prognostic model. RESULTS The results showed that the MC1 subtype had a poor prognosis based on higher immune activity and immune checkpoint gene expression. The MC2 subtype is associated with high metabolic activity and low expression of immune checkpoint genes and a better prognosis. The MC2 subtype was more responsive to PD-L1 immunotherapy than the MC1 subclass. However, we did not observe significant differences in tumor mutational burden between the two. CONCLUSION Two molecular subtypes of colon cancer based on metabolic pathways have distinct immune signatures. Constructing prognostic models based on subtype differential genes provides valuable reference for personalized therapy targeting unique tumor metabolic signatures.
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Affiliation(s)
- Zhujiang Dai
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Xiang Peng
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Yuegui Guo
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Xia Shen
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Wenjun Ding
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Jihong Fu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Zhonglin Liang
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. .,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.
| | - Jinglue Song
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. .,Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.
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Schiff JP, Chin RI, Roy A, Mahapatra L, Stowe HB, Andruska N, Huang Y, Mutch M, Fields RC, Hawkins WG, Doyle M, Chapman W, Tan B, Henke LE, Badiyan SN, DeSelm C, Samson PP, Pedersen K, Kim H. Oligometastatic Rectal Adenocarcinoma Treated with Short-Course Radiotherapy and Chemotherapy with Nonoperative Intent of the Primary for Locoregional Complete Responders. Pract Radiat Oncol 2022; 12:e406-e414. [PMID: 35526826 DOI: 10.1016/j.prro.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/07/2022] [Accepted: 04/21/2022] [Indexed: 11/11/2022]
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Talebi A, Rokni P, Kerachian MA. Transcriptome analysis of colorectal cancer liver metastasis: The importance of long non-coding RNAs and fusion transcripts in the disease pathogenesis. Mol Cell Probes 2022; 63:101816. [DOI: 10.1016/j.mcp.2022.101816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/21/2022] [Accepted: 03/29/2022] [Indexed: 11/16/2022]
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A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer. Cancers (Basel) 2021; 14:cancers14010136. [PMID: 35008299 PMCID: PMC8750372 DOI: 10.3390/cancers14010136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/14/2021] [Accepted: 12/20/2021] [Indexed: 12/02/2022] Open
Abstract
Simple Summary A gene signature derived from the loss of CDKN1A (p21) gene, obtained in HCT116 p21-/- colorectal cancer cells, is identified in a large cohort of primary colorectal (CRC) tumors and is associated with the Consensus Molecular Subtype (CMS) of colon cancer that has a worse relapse-free and overall survival, that is, CMS4 (also called mesenchymal subtype). The presented gene signature can help to uncover the early molecular mechanisms of epithelial–mesenchymal transition (EMT), which is known to be associated with high stemness and drug resistance. Abstract The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.
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Evaluation of a 55-gene classifier as a prognostic biomarker for adjuvant chemotherapy in stage III colon cancer patients. BMC Cancer 2021; 21:1332. [PMID: 34906120 PMCID: PMC8672629 DOI: 10.1186/s12885-021-09088-6] [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: 06/01/2021] [Accepted: 11/18/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Adjuvant chemotherapy reduces the risk of recurrence of stage III colon cancer (CC). However, more effective prognostic and predictive biomarkers are needed for better treatment stratification of affected patients. Here, we constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. METHODS We retrospectively identified patients aged 20-79 years, with stage III CC, who received adjuvant chemotherapy with or without oxaliplatin, between the years 2009 and 2012. RESULTS Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity score matching. Of these, 95 patients from each group were analyzed, and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7 and 77.1%, respectively. The hazard ratios for 5-year RFS following adjuvant chemotherapy (fluoropyrimidine), with and without oxaliplatin, were 1.241 (95% CI, 0.465-3.308; P = 0.67) and 0.791 (95% CI, 0.329-1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3 and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145-1.692; P = 0.25). No differences in RFS rates were noted in the CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in patients with left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates of the MSI-like subtype in left-sided cancer patients were 100 and 53.9% with and without oxaliplatin, respectively. CONCLUSIONS Subclassification using 55GC and tumor sidedness revealed increased RFS in patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine and oxaliplatin compared to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. TRIAL REGISTRATION The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID: 000023879 ).
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Abstract
Colorectal cancer (CRC) is still one of the most common types of cancer in the world, and the gut microbiome plays an important role in its development. The microbiome is involved in the carcinogenesis, formation and progression of CRC as well as its response to different systemic therapies. The composition of bacterial strains and the influence of geography, race, sex, and diet on the composition of the microbiome serve as important information for screening, early detection and prediction of the treatment outcome of CRC. Microbiome modulation is one of the most prospective new strategies in medicine to improve the health of individuals. Therefore, future research and clinical trials on the gut microbiome in oncology as well as in the treatment of CRC patients are warranted to determine the efficacy of systemic treatments for CRC, minimize adverse effects and increase survival rates.
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Affiliation(s)
- Martina Rebersek
- Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000, Ljubljana, Slovenia. .,Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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Azcue P, Guerrero Setas D, Encío I, Ibáñez-Beroiz B, Mercado M, Vera R, Gómez-Dorronsoro ML. A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma. Cancers (Basel) 2021; 13:5909. [PMID: 34885019 PMCID: PMC8656725 DOI: 10.3390/cancers13235909] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/09/2022] Open
Abstract
Molecular characterization of colorectal cancer has helped us understand better the biology of the disease. However, previous efforts have yet to provide significant clinical value in order to be integrated into clinical practice for patients with early-stage colon cancer (CC). The purpose of this study was to assess PD-L1, GLUT-1, e-cadherin, MUC2, CDX2, and microsatellite instability (dMMR) and to propose a risk-panel with prognostic capabilities. Biomarkers were immunohistochemically assessed through tissue microarrays in a cohort of 144 patients with stage II/III colon cancer. A biomarker panel consisting of PD-L1, GLUT-1, dMMR, and potentially CDX2 was constructed that divided patients into low, medium, and high risk of overall survival or disease-free survival (DFS) in equally sized groups. Compared with low-risk patients, medium-risk patients have almost twice the risk of death (HR = 2.10 (0.99-4.46), p = 0.054), while high-risk patients have almost four times the risk (HR = 3.79 (1.77-8.11), p = 0.001). The multivariate goodness of fit was 0.756 and was correlated with Kaplan-Meier curves (p = 0.002). Consistent results were found for DFS. This study provides a critical basis for the future development of an immunohistochemical assessment capable of discerning early-stage CC patients as a function of their prognosis. This tool may aid with treatment personalization in daily clinical practice and improve survival outcomes.
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Affiliation(s)
- Pablo Azcue
- Department of Health Science, Public University of Navarra, 31008 Pamplona, Spain; (I.E.); (B.I.-B.)
| | - David Guerrero Setas
- Department of Pathology, University Hospital of Navarra, 31008 Pamplona, Spain; (D.G.S.); (M.M.)
- Campus Arrosadia, Public University of Navarra, 31006 Pamplona, Spain
- Molecular Pathology of Cancer Group–Navarrabiomed, 31008 Pamplona, Spain
- Department of Medical Oncology, University Hospital of Navarra, 31008 Pamplona, Spain;
| | - Ignacio Encío
- Department of Health Science, Public University of Navarra, 31008 Pamplona, Spain; (I.E.); (B.I.-B.)
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
| | - Berta Ibáñez-Beroiz
- Department of Health Science, Public University of Navarra, 31008 Pamplona, Spain; (I.E.); (B.I.-B.)
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
- Unit of Methodology-Navarrabiomed-University Hospital of Navarra, 31008 Pamplona, Spain
- Research Network on Health Services Research and Chronic Diseases (REDISSEC), 31008 Pamplona, Spain
| | - María Mercado
- Department of Pathology, University Hospital of Navarra, 31008 Pamplona, Spain; (D.G.S.); (M.M.)
| | - Ruth Vera
- Department of Medical Oncology, University Hospital of Navarra, 31008 Pamplona, Spain;
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
| | - María Luisa Gómez-Dorronsoro
- Department of Pathology, University Hospital of Navarra, 31008 Pamplona, Spain; (D.G.S.); (M.M.)
- Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain
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Valenzuela G, Canepa J, Simonetti C, Solo de Zaldívar L, Marcelain K, González-Montero J. Consensus molecular subtypes of colorectal cancer in clinical practice: A translational approach. World J Clin Oncol 2021; 12:1000-1008. [PMID: 34909395 PMCID: PMC8641009 DOI: 10.5306/wjco.v12.i11.1000] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/11/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
The identification of several genetic mutations in colorectal cancer (CRC) has allowed a better comprehension of the prognosis and response to different antineoplastic treatments. Recently, through a systematic process, consensus molecular subtypes (CMS) have been described to characterize genetic and molecular mutations in CRC patients. Through CMS, CRC patients can be categorized into four molecular subtypes of CRC by wide transcriptional genome analysis. CMS1 has microsatellite instability and mutations in CIMP and BRAF pathways. CMS2, distinguished by mutations in specific pathways linked to cellular metabolism, also has a better prognosis. CMS3 has a KRAS mutation as a hallmark. CMS4 presents mutations in fibrogenesis pathways and mesenchymal-epithelial transition, associated with a worse prognosis. CMS classification can be a meaningful step in providing possible answers to important issues in CRC, such as the use of adjuvant chemotherapy in stage II, personalized first-line chemotherapy for metastasic CRC, and possible new target treatments that address specific pathways in each molecular subtype. Understanding CMS is a crucial step in personalized medicine, although prospective clinical trials selecting patients by CMS are required to pass proof-of-concept before becoming a routine clinical tool in oncology routine care.
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Affiliation(s)
- Guillermo Valenzuela
- Basic and Clinical Oncology Department, University of Chile, Santiago 8380453, Chile
| | - Joaquín Canepa
- Basic and Clinical Oncology Department, University of Chile, Santiago 8380453, Chile
| | - Carolina Simonetti
- Basic and Clinical Oncology Department, University of Chile, Santiago 8380453, Chile
| | | | - Katherine Marcelain
- Basic and Clinical Oncology Department, University of Chile, Santiago 8380453, Chile
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APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes. Cancers (Basel) 2021; 13:cancers13215394. [PMID: 34771559 PMCID: PMC8582550 DOI: 10.3390/cancers13215394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/03/2021] [Accepted: 10/25/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is a major cause of cancer deaths. Cetuximab is an FDA-approved, underutilized therapeutic targeting the epidermal growth factor receptor (EGFR) in metastatic CRC. To date, despite selection of patients with wild-type RAS, it is still difficult to identify patients who may benefit from EGFR inhibitor (e.g., cetuximab) therapy. Our aim is to molecularly classify CRC patients to better identify subpopulations sensitive to EGFR targeted therapy. APC and TP53 are two major tumor suppressor genes in CRC whose mutations contribute to tumor initiation and progression and may identify cetuximab-sensitive tumors. Recently, it has been suggested that the consensus molecular subtype (CMS) classification may be used to help identify cetuximab-sensitive patients. Here, we report an analysis of multiple CRC tumor/PDX/cell line datasets using combined APC and TP53 mutations to refine the CMS classification to better predict responses to cetuximab to improve patient outcomes. Abstract Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across all CMS classes. Similar results were also obtained in independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.
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Kanani A, Veen T, Søreide K. Neoadjuvant immunotherapy in primary and metastatic colorectal cancer. Br J Surg 2021; 108:1417-1425. [PMID: 34694371 PMCID: PMC10364874 DOI: 10.1093/bjs/znab342] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/07/2021] [Accepted: 09/02/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is the second most common solid organ cancer. Traditional treatment is with surgery and chemotherapy. Immunotherapy has recently emerged as a neoadjuvant therapy that could change treatment strategy in both primary resectable and metastatic CRC. METHODS A literature review of PubMed with a focus on studies exploring upfront immunotherapy in operable CRC, either for primary resectable stage I-III cancers or for (potentially) operable liver metastasis. RESULTS Immune checkpoint blockade by the programmed cell death 1 (PD-1) receptor inhibitors nivolumab and pembrolizumab and the cytotoxic T cell-associated protein 4 (CTLA-4) inhibitor ipilimumab has shown good results in both early-stage and advanced CRC. The effects of immune checkpoint inhibitors have so far been demonstrated in small phase I/II studies and predominantly in treatment-refractory stage IV disease with defect Mismatch repair (dMMR). However, recent data from phase I/II (NICHE-1) studies suggest an upfront role for immunotherapy in operable stage I-III disease. By blocking crucial immune checkpoints, cytotoxic T cells are activated and release cytotoxic signals that initiate cancer cell destruction. The very high complete response rate in dMMR operable CRC with neoadjuvant immunotherapy with nivolumab and ipilimumab, and even partial pathological response in some patients with proficient MMR (pMMR) CRC, calls for further attention to patient selection for neoadjuvant treatment, beyond MMR status alone. CONCLUSION Early data on the effect of immunotherapy in CRC provide new strategic thinking of treatment options in CRC for both early-stage and advanced disease, with prospects for new trials.
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Affiliation(s)
- A Kanani
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Department of Gastrointestinal Surgery, Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
| | - T Veen
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Department of Gastrointestinal Surgery, Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
| | - K Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.,Department of Gastrointestinal Surgery, Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Wusterbarth E, Chen Y, Jecius H, Krall E, Runyan RB, Pandey R, Nfonsam V. Cartilage Oligomeric Matrix Protein, COMP may be a Better Prognostic Marker Than CEACAM5 and Correlates With Colon Cancer Molecular Subtypes, Tumor Aggressiveness and Overall Survival. J Surg Res 2021; 270:169-177. [PMID: 34687957 DOI: 10.1016/j.jss.2021.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 08/30/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND New tumor biomarkers are needed to improve the management of Colon cancer (CC), the second leading cause of cancer-related deaths in the United States. Carcinoembryonic Antigen (CEA), the translated protein of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) gene, is used as a biomarker for CC. Cartilage Oligomeric Matrix Protein (COMP) is overexpressed in CC compared to normal colon tissues. This study aims to evaluate the expression of COMP by disease stage, consensus molecular subtype (CMS), its impact on disease outcomes, and comparison to CEACAM5. MATERIALS AND METHODS RNA-seq data from 456 CC The Cancer Genome Atlas samples and 41 matching control samples were analyzed for COMP expression and CEACAM5 expression. We stratified tumor samples by stage (I-IV), subtype (CMS1-CMS4), tumor location, and Kirsten RAt Sarcoma (KRAS) mutant status and three quartiles were established based on COMP expression. Kaplan Meier survival outcomes were evaluated. RESULTS COMP expression was significantly higher in tumor samples, with elevation of expression occurring in stage I and significantly increasing in stage IV. Increased COMP expression occurs in CMS4 with relatively low expression in CMS3. No significant expression difference was attributed to tumor location and KRAS mutant status. Compared to CEACAM5, COMP was a stronger molecular marker across stages and subtypes. CMS4 was associated with the high COMP expression, and higher levels of COMP were associated with poorer overall survival, disease-specific survival, and tumor progression-free intervals. CMS2 and 3 were associated with low expression and better survival. CONCLUSION COMP is a potential molecular biomarker for CC and may be superior to CEA as an indicator of CC.
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Affiliation(s)
- Emily Wusterbarth
- Department of Surgery, University of Arizona Medical Center, Tucson, Arizona
| | - Yuliang Chen
- University of Arizona Cancer Center, Tucson, Arizona
| | - Hunter Jecius
- Department of Surgery, University of Arizona Medical Center, Tucson, Arizona
| | - Erika Krall
- Department of Surgery, University of Arizona Medical Center, Tucson, Arizona
| | - Raymond B Runyan
- Department of Cellular and Molecular Medicine, University of Arizona Medical Center, Tucson, Arizona
| | - Ritu Pandey
- University of Arizona Cancer Center, Tucson, Arizona; Department of Cellular and Molecular Medicine, University of Arizona Medical Center, Tucson, Arizona
| | - Valentine Nfonsam
- Department of Surgery, University of Arizona Medical Center, Tucson, Arizona.
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Chowdhury S, Hofree M, Lin K, Maru D, Kopetz S, Shen JP. Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer. Cancers (Basel) 2021; 13:4923. [PMID: 34638407 PMCID: PMC8507736 DOI: 10.3390/cancers13194923] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/21/2021] [Accepted: 09/25/2021] [Indexed: 01/04/2023] Open
Abstract
The implications of intratumor heterogeneity on the four consensus molecular subtypes (CMS) of colorectal cancer (CRC) are not well known. Here, we use single-cell RNA sequencing (scRNASeq) to build an algorithm to assign CMS classification to individual cells, which we use to explore the distributions of CMSs in tumor and non-tumor cells. A dataset of colorectal tumors with bulk RNAseq (n = 3232) was used to identify CMS specific-marker gene sets. These gene sets were then applied to a discovery dataset of scRNASeq profiles (n = 10) to develop an algorithm for single-cell CMS (scCMS) assignment, which recapitulated the intrinsic biology of all four CMSs. The single-cell CMS assignment algorithm was used to explore the scRNASeq profiles of two prospective CRC tumors with mixed CMS via bulk sequencing. We find that every CRC tumor contains individual cells of each scCMS, as well as many individual cells that have enrichment for features of more than one scCMS (called mixed cells). scCMS4 and scCMS1 cells dominate stroma and immune cell clusters, respectively, but account for less than 3% epithelial cells. These data imply that CMS1 and CMS4 are driven by the transcriptomic contribution of immune and stromal cells, respectively, not tumor cells.
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Affiliation(s)
- Saikat Chowdhury
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (K.L.); (S.K.)
| | - Matan Hofree
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Kangyu Lin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (K.L.); (S.K.)
| | - Dipen Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (K.L.); (S.K.)
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (K.L.); (S.K.)
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49
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Stahler A, Heinemann V, Schuster V, Heinrich K, Kurreck A, Gießen-Jung C, Fischer von Weikersthal L, Kaiser F, Decker T, Held S, Graeven U, Schwaner I, Denzlinger C, Schenk M, Neumann J, Kirchner T, Jung A, Kumbrink J, Stintzing S, Modest DP. Consensus molecular subtypes in metastatic colorectal cancer treated with sequential versus combined fluoropyrimidine, bevacizumab and irinotecan (XELAVIRI trial). Eur J Cancer 2021; 157:71-80. [PMID: 34507244 DOI: 10.1016/j.ejca.2021.08.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy. MATERIAL AND METHODS Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival. RESULTS CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33-0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29-0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41-0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20-0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012) CONCLUSIONS: In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri. TRIAL REGISTRATION Trial registration ID (clinicaltrials.gov) NCT01249638.
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Affiliation(s)
- Arndt Stahler
- Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumour Immunology, Charitéplatz 1, 10117, Berlin, Germany.
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU, Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Veronika Schuster
- Department of Medicine III, University Hospital, LMU, Munich, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, LMU, Munich, Germany
| | - Annika Kurreck
- Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumour Immunology, Charitéplatz 1, 10117, Berlin, Germany
| | | | | | | | | | | | - Ullrich Graeven
- Department of Hematology, Oncology and Gastroenterology, Kliniken Maria Hilf GmbH, Mönchengladbach, Germany
| | - Ingo Schwaner
- Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany
| | | | - Michael Schenk
- Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Jens Neumann
- Institute of Pathology, University of Munich, Germany
| | - Thomas Kirchner
- LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University of Munich, Germany
| | - Andreas Jung
- LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University of Munich, Germany
| | - Jörg Kumbrink
- LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University of Munich, Germany
| | - Sebastian Stintzing
- Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumour Immunology, Charitéplatz 1, 10117, Berlin, Germany; Charité - Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik P Modest
- Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumour Immunology, Charitéplatz 1, 10117, Berlin, Germany; Charité - Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
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50
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Moosavi SH, Eide PW, Eilertsen IA, Brunsell TH, Berg KCG, Røsok BI, Brudvik KW, Bjørnbeth BA, Guren MG, Nesbakken A, Lothe RA, Sveen A. De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity. Genome Med 2021; 13:143. [PMID: 34470666 PMCID: PMC8411513 DOI: 10.1186/s13073-021-00956-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 08/17/2021] [Indexed: 12/17/2022] Open
Abstract
Background Gene expression-based subtyping has the potential to form a new paradigm for stratified treatment of colorectal cancer. However, current frameworks are based on the transcriptomic profiles of primary tumors, and metastatic heterogeneity is a challenge. Here we aimed to develop a de novo metastasis-oriented framework. Methods In total, 829 transcriptomic profiles from patients with colorectal cancer were analyzed, including primary tumors, liver metastases, and non-malignant liver samples. High-resolution microarray gene expression profiling was performed of 283 liver metastases from 171 patients treated by hepatic resection, including multiregional and/or multi-metastatic samples from each of 47 patients. A single randomly selected liver metastasis sample from each patient was used for unsupervised subtype discovery by nonnegative matrix factorization, and a random forest prediction model was trained to classify multi-metastatic samples, as well as liver metastases from two independent series of 308 additional patients. Results Initial comparisons with non-malignant liver samples and primary colorectal tumors showed a highly variable degree of influence from the liver microenvironment in metastases, which contributed to inter-metastatic transcriptomic heterogeneity, but did not define subtype distinctions. The de novo liver metastasis subtype (LMS) framework recapitulated the main distinction between epithelial-like and mesenchymal-like tumors, with a strong immune and stromal component only in the latter. We also identified biologically distinct epithelial-like subtypes originating from different progenitor cell types. LMS1 metastases had several transcriptomic features of cancer aggressiveness, including secretory progenitor cell origin, oncogenic addictions, and microsatellite instability in a microsatellite stable background, as well as frequent RAS/TP53 co-mutations. The poor-prognostic association of LMS1 metastases was independent of mutation status, clinicopathological variables, and current subtyping frameworks (consensus molecular subtypes and colorectal cancer intrinsic subtypes). LMS1 was also the least heterogeneous subtype in comparisons of multiple metastases per patient, and tumor heterogeneity did not confound the prognostic value of LMS1. Conclusions We report the first large study of multi-metastatic gene expression profiling of colorectal cancer. The new metastasis-oriented subtyping framework showed potential for clinically relevant transcriptomic classification in the context of metastatic heterogeneity, and an LMS1 mini-classifier was constructed to facilitate prognostic stratification and further clinical testing. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-021-00956-1.
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Affiliation(s)
- Seyed H Moosavi
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. box 1171 Blindern, NO-0318, Oslo, Norway
| | - Peter W Eide
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway
| | - Ina A Eilertsen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. box 1171 Blindern, NO-0318, Oslo, Norway
| | - Tuva H Brunsell
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway
| | - Kaja C G Berg
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway
| | - Bård I Røsok
- K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. box 4950, NO-0424, Oslo, Norway
| | - Kristoffer W Brudvik
- K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. box 4950, NO-0424, Oslo, Norway
| | - Bjørn A Bjørnbeth
- K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. box 4950, NO-0424, Oslo, Norway
| | - Marianne G Guren
- K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Department of Oncology, Oslo University Hospital, P.O. box 4953, NO-0424, Oslo, Norway
| | - Arild Nesbakken
- K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. box 1171 Blindern, NO-0318, Oslo, Norway.,Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. box 4950, NO-0424, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. box 1171 Blindern, NO-0318, Oslo, Norway
| | - Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. box 4953 Nydalen, NO-0424, Oslo, Norway. .,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, P.O. Box 4953 Nydalen, NO-0424, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. box 1171 Blindern, NO-0318, Oslo, Norway.
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