• 3D model
• cancer‐associated fibroblast
• ovarian cancer
• tumor microenvironment

• Aerobic glycolysis
• EFEMP2/Wnt/β-catenin
• MFAP5
• PTC
• Proliferation

• Humans
• Thyroid Cancer, Papillary/pathology
• Thyroid Cancer, Papillary/metabolism
• Thyroid Cancer, Papillary/genetics
• Wnt Signaling Pathway/physiology
• Animals
• Thyroid Neoplasms/pathology
• Thyroid Neoplasms/metabolism
• Thyroid Neoplasms/genetics
• Mice, Nude
• Cell Proliferation
• Mice
• Disease Progression
• Glycolysis
• Extracellular Matrix Proteins/metabolism
• Extracellular Matrix Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor
• Female
• Male
• Warburg Effect, Oncologic

• Heterogeneity
• ScRNA-seq
• Treatment resistance
• ovarian cancer
• tumour microenvironment

• Humans
• Ovarian Neoplasms/genetics
• Single-Cell Analysis
• Female
• Sequence Analysis, RNA/methods
• Tumor Microenvironment/genetics
• Animals

• AKT/mTOR
• EMT
• MFAP5
• endometrial cancer
• proliferation

• cell line
• cluster analysis
• drug development
• ovarian cancer
• ovarian carcinoma
• signal transduction pathway

• STIM-00107 OPZUID

• Adipocytes
• Body Mass Index
• Breast
• Extracellular matrix
• Fibroblasts
• Galectin
• LGALS1
• LGALS3
• Obesity
• PXDN
• Peroxidasin
• Stromal cells
• Tissue Proteomics
• Tumor Microenvironment

• R01 CA258766 NCI NIH HHS

• desloratadine
• endosomal escape
• hepatocellular carcinoma
• polyion complex micelles
• polypept(o)ides
• siRNA co‐delivery

• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/metabolism
• RNA, Small Interfering/chemistry
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Animals
• Micelles
• Mice
• Cancer-Associated Fibroblasts/metabolism
• Cancer-Associated Fibroblasts/drug effects
• Humans
• Cell Line, Tumor

• SFB1066-3 German Research Foundation

• RNA-seq
• dog
• melanoma
• radiotherapy
• temozolomide

• Dogs
• Animals
• Mouth Neoplasms/genetics
• Mouth Neoplasms/veterinary
• Mouth Neoplasms/radiotherapy
• Mouth Neoplasms/pathology
• Melanoma/genetics
• Melanoma/radiotherapy
• Melanoma/veterinary
• Melanoma/pathology
• Dog Diseases/genetics
• Dog Diseases/radiotherapy
• Transcriptome
• Gene Expression Regulation, Neoplastic
• Tumor Microenvironment/genetics
• Tumor Microenvironment/radiation effects
• Male
• Gene Expression Profiling/methods
• Female

• IZSVe 11/13 RC Italian Ministry of Health
• DOR1877477 University of Padua

• Chemotherapy resistance
• Non-cellular components
• Ovarian cancer
• TME
• Tumor microenvironment

• Humans
• Female
• Tumor Microenvironment/physiology
• Clinical Relevance
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/pathology

• Heritable thoracic aortic aneurysm
• MFAP5
• case report
• whole-exome sequencing

• AP-1
• UGT2B15
• androgen receptor
• esophageal squamous cell carcinoma
• invasion
• metastasis

• 7212085 Beijing Natural Science Foundation
• 2021-I2M-1-018; 2021-I2M-1-067 the CAMS Innovation Fund for Medical Sciences
• 3332021091 the Fundamental Research Funds for the Central Universities
• 3332023138 the Special Research Fund for Central Universities, Peking Union Medical College

• cancer
• computational biology and bioinformatics

• Humans
• Transcriptome
• Tissue Inhibitor of Metalloproteinase-1/genetics
• Squamous Cell Carcinoma of Head and Neck
• Gene Expression Profiling
• Head and Neck Neoplasms
• Tumor Microenvironment/genetics

• advanced ovarian cancer
• anticancer therapy
• bepridil
• epithelial–mesenchymal transition
• metastasis

• RS-2022-00165497 National Research Foundation of Korea
• 2019R1A5A2027588 National Research Foundation of Korea
• 2020R1H1A1102285 National Research Foundation of Korea

• cell biology
• cell migration
• cell signalling
• cytoskeleton
• mechanisms of disease

• Animals
• Mice
• Cicatrix/pathology
• Fibroblasts/metabolism
• Fibrosis
• Microfibrils
• Skin/metabolism
• Wound Healing/physiology
• Intercellular Signaling Peptides and Proteins/metabolism
• Contractile Proteins/metabolism

• GM50875 NIH HHS
• F31 AR082287 NIAMS NIH HHS
• DE028747-01 NIH HHS
• AR082287-01 NIH HHS
• R35 GM139603 NIGMS NIH HHS
• National Institutes of Health

• Extracellular matrix
• Head and neck squamous cell carcinoma
• Migration
• Proliferation
• Tumour invasion
• Tumour micro-environment

• Anti-TNNT1
• Biomarker
• Epithelial–mesenchymal transition
• Hepatocellular carcinoma
• Slow skeletal muscle troponin T

• Humans
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Liver Neoplasms/pathology
• Troponin T/genetics
• Prognosis
• Cell Movement/genetics
• Muscle, Skeletal/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor

• circRNAs
• fertility
• goat
• litter size
• lncRNAs

• Animals
• Pregnancy
• Female
• RNA, Messenger/genetics
• RNA, Circular
• RNA, Long Noncoding/genetics
• Gene Expression Profiling
• Goats/genetics
• Litter Size/genetics
• Hypothalamus

• NK cells
• T cells
• decidual stromal cells
• macrophages
• maternal-fetal interface
• single-cell RNA sequencing
• trophoblast cell

• N-glycoproteomics
• cancer-associated fibroblast
• high-grade serous ovarian cancer
• mass spectrometry
• proteomics
• tumor microenvironment

• CSIOVDB
• Kaplan-Meier plotter
• MAGP2
• MFAP5
• cBioPortal
• immunohistochemistry
• microfibril-associated glycoprotein 2
• microfibril-associated protein 5
• ovarian cancer
• prognostic markers
• string

• E2F1
• Gastric cancer
• Smad signaling
• TGF-β
• Troponin C-1

Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity.

Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro.

BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes.

BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy.

• Gene Expression Profiling
• Immunoassay
• Immunotherapy
• Lymphocytes, Tumor-Infiltrating
• Tumor Microenvironment

• Allografts/pathology
• Fibroblasts/pathology
• Fibrosis
• Graft Rejection
• Humans
• Kidney/pathology
• Kidney Diseases/pathology
• Kidney Transplantation
• Living Donors
• Transcriptome

• R37 AI051652 NIAID NIH HHS
• R01 AI051652 NIAID NIH HHS
• R03 DK105270 NIDDK NIH HHS
• UL1 TR000457 NCATS NIH HHS
• K08 DK087824 NIDDK NIH HHS
• National Institutes of Health

• ELI
• PDAC
• cancer dissemination
• cancer stroma
• cancer stroma interaction
• cancer-associated fibroblasts
• fibroblast
• initiation of metastasis
• pancreatic ductal cell carcinoma
• stromal invasibility

• R37 CA248161 NCI NIH HHS
• R37-CA248161 NCI NIH HHS

• TGFBR1
• gene ontology
• granulosa cell tumors
• signaling pathways

• R03 HD082416 NICHD NIH HHS
• R03HD082416 Eunice Kennedy Shriver National Institute of Child Health and Human Development
• P30 ES029067 NIEHS NIH HHS
• R03CA235001 NCI NIH HHS
• R03 CA235001 NCI NIH HHS

The tumor microenvironment (TME) is essential for immune escape by tumor cells. It plays essential roles in tumor development and metastasis. The clinical outcomes of tumors are often closely related to individual differences in the patient TME. Therefore, reprogramming TME cells and their intercellular communication is an attractive and promising strategy for cancer therapy. TME cells consist of immune and nonimmune cells. These cells need to be manipulated precisely and safely to improve cancer therapy. Furthermore, it is encouraging that this field has rapidly developed in recent years with the advent and development of gene editing technologies. In this review, we briefly introduce gene editing technologies and systematically summarize their applications in the TME for precision cancer therapy, including the reprogramming of TME cells and their intercellular communication. TME cell reprogramming can regulate cell differentiation, proliferation, and function. Moreover, reprogramming the intercellular communication of TME cells can optimize immune infiltration and the specific recognition of tumor cells by immune cells. Thus, gene editing will pave the way for further breakthroughs in precision cancer therapy.

• GnRH agonist
• anti-estrogen
• aromatase inhibitors
• gynecological cancers
• hormonal therapy

• Ca2+/calmodulin-dependent protein kinase II
• Cancer-associated fibroblast
• Colorectal cancer
• Fibroblast
• TGFβ1

The natural incidence of primary epithelial ovarian cancer (OVC) in adult female voles of some established strains of Microtus fortis is relatively high. M. fortis OVC has some pathological similarities to human epithelial OVC, therefore M. fortis represents the latest and most valuable animal model for studying human OVC. The lack of available genetic information for M. fortis limits the use of common immunological methods; thus, high-throughput sequencing technologies have been used to reveal the mechanisms of primary OVC in M. fortis. The individuals with cancer were diagnosed using histopathologic hematoxylin and eosin staining. The present study used RNA-sequencing (RNA-seq) technology to establish a de novo assembly of the M. fortis transcriptome produced 339,830 unigenes by the short reads assembly program Trinity. Comparisons were made between OVC and healthy ovarian tissue (OV) and between fallopian tube cancer (FTC) and healthy fallopian tube (FT) tissues using RNA-seq analysis. A total of 3,434 differentially expressed genes (DEGs) were identified in OVC tissue compared with OV tissue using RNA-Seq by Expectation-Maximization software, including 1,950 significantly upregulated and 1,484 significantly downregulated genes. There were 2,817 DEGs identified in the FTC tissues compared with the FT tissue, including 1,762 significantly upregulated and 1,055 significantly downregulated genes. Pathway enrichment analysis revealed that upregulated transcripts in the OVC vs. OV groups were involved in cell growth and proliferation-associated pathways, whereas the downregulated DEGS in the OVC vs. OV groups were enriched in steroid biosynthesis-related pathways. Furthermore, the tumor suppressor gene, p53, was downregulated in the FTC and OVC compared with the FT and OV groups, respectively; whereas, genes that promoted cell migration, such as Ras-related protein Rap-1b, Ras homolog family member A and RAC1, were upregulated. In summary, to the best of our knowledge, the present study characterized the M. fortis de novo transcriptome of OV and FT tissues and to perform RNA-seq quantification to analyze the differences in healthy and cancerous OV and FT tissues. These results identified pathways that differed between cancerous and healthy M. fortis tissues. Analysis of these pathways may help to reveal the pathogenesis of primary OVC in M. fortis in future work.

• Microtus fortis
• RNA‑sequencing
• epithelial ovarian cancer
• primary ovarian cancer

Metastasis is still the primary cause of cancer-related mortality. However, the underlying mechanisms of cancer metastasis are not yet fully understood. Currently, the epithelial-mesenchymal transition, metabolic remodeling, cancer cell intercommunication and the tumor microenvironment including diverse stromal cells, are reported to affect the metastatic process of cancer cells. Calcium ions (Ca²⁺) are ubiquitous second messengers that manipulate cancer metastasis by affecting signaling pathways. Diverse transporter/pump/channel-mediated Ca²⁺ currents form Ca²⁺ oscillations that can be decoded by Ca²⁺-binding proteins, which are promising prognostic biomarkers and therapeutic targets of cancer metastasis. This paper presents a review of the advances in research on the mechanisms underlying cancer metastasis and the roles of Ca²⁺-related signals in these events.

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF “state.” Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e⁺ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low–specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.

• AKT/GSK-3β/SNAIL signaling
• Epithelial-mesenchymal transition (EMT)
• Ovarian cancer
• Troponin C type 1 (TNNC1)

• CDK1
• cell proliferation
• high throughput RNA-seq
• ovarian cancer
• sinomenine

• LukS-PV
• TNNC1/PI3K/AKT axis
• hepatocellular carcinoma
• migration

As we know, chemotherapy resistance is a critical factor leading to recurrence and metastasis of nonsmall-cell lung cancer (NSCLC). To clarify the key target and potential mechanism of resistance to gemcitabine (GEM) in NSCLC, we selected Gene Expression Omnibus Data Set and statistically analyzed a parent cell group and a GEM-resistant cell group. Results showed that the expression of troponin C1, slow skeletal and cardiac type (TNNC1) in GEM-resistant cells was higher than in parent cells, which implies that TNNC1 was associated with GEM resistance in lung cancer cells.

TNNC1 expression level was detected by reverse transcription-quantitative polymerase chain reaction or western blot in GEM-resistant patient serum and cell lines. It could reduce or increase autophagy response and GEM resistance accordingly by inhibition of the short interfering ribonucleic acid or by forced overexpression of TNNC1 viruses in A549 cell line and GEM-resistant cell line (A549/GemR) respectively. Blocking autophagy with 3-methyladenine increased the sensitivity of chemotherapy confirmed by flow cytometry and microtubule-associated protein 1A/1B – light chain 3 punctate assay. What’s more, in a loss-of-function model, silencing of forkhead box 03 (FOXO3) in A549/GemR cells could rescue the autophagy weakened by TNNC1.

TNNC1 promoted GEM chemoresistance of NSCLC by activating cytoprotective autophagy, regulated negatively by FOXO3. This research may provide a completely new strategy for NSCLC treatment.

Targeting the TNNC1/FOXO3 signaling pathway in NSCLC may be a novel strategy to combat GEM resistance.

• Desmoplasia
• Gallbladder adenocarcinoma
• Invasion
• MFAP5

Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian cancer metastases are a consequence of the crosstalk between cancer cells and the tumour microenvironment by soluble factors and extracellular vesicles. Characterisation of the alterations in both the tumour cells and the surrounding microenvironment has emerged as a new research field to understand ovarian cancer metastasis. In this mini review, we will summarise the most recent findings, focusing our attention on the role of secreted factors and extracellular vesicles in ovarian cancer metastasis.

•

During ovarian cancer metastasis, tumour cells metastasise in the mesothelium as primarily ‘soil’ for ovarian cancer ‘seeds’.

• Cancer
• Exosomes
• Extracellular vesicles
• Metastasis

• calcium signaling
• drug resistance
• organelles
• ovarian cancer

• PN-III-P1-1.2-PCCDI-2017-0833/ 68/2018 Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii

Several serum biomarkers, including miRNA, mRNA, protein and peptides in cancer patients are also important mediators of cancer progression.

The differentially expressed peptides between the serum of ovarian cancer patients and healthy controls were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The function of the peptides was analyzed by CCK8, transwell, wound healing, and flow cytometry analysis. And the mechanism of the peptides was analyzed by peptide pull down, and high-throughput RNA-sequencing.

A total of 7 and 46 peptides were significantly up-regulated and down-regulated in the serum of ovarian cancer patients, respectively. The precursor proteins of the differentially expressed peptides mainly involved in the complement and coagulation cascades, platelet activation, phagosome and focal adhesion pathways. Interestingly, focal adhesion, platelet activation, platelet-cancer cell interaction, complement activation, coagulation cascades and phagosome formation are all critical factors for cancer initiation or progression, which indicated that the peptides may play a crucial role in cancer development. And we identified one peptide, ZYX_36-58, which was down-regulated in the serum of ovarian cancer patients, significantly inhibited invasion and migration and promoted the apoptosis of ovarian cancer cells. Mechanistic study indicated that ZYX_36-58 interacted with and increased the protein level of the antiangiogenic protein thrombospondin-1 (TSP1), which has a tumor suppressive effect on ovarian cancer.

ZYX_36-58, which was significantly down-regulated in the serum of ovarian cancer patients can significantly inhibit cell invasion, migration and promote apoptosis of ovarian cancer cells by binding and up-regulating TSP1 protein expression.

• Peptidome
• TSP1
• ZYX36-58
• migration
• ovarian cancer (OC)