Work

TGF-βI/FERMT2 / COL6A1 Reciprocal Loop Drives Tumor-Stroma Crosstalk and Promotes Peritoneal Metastasis in Gastric Cancer

Year: 2025

Type: article

Abstract: Background: Peritoneal metastasis (PM) is a frequent and fatal progression in advanced gastric cancer (GC), shaped by intricate interactions between tumor cells and the tumor microenvironment.Among these, gastric cancer-associated fibroblasts (GCAFs) are key mediators of tumor progression, yet the molecular regulators underlying tumor-stroma crosstalk remain poorly defined.Methods: We combined bulk and single-cell transcriptomics, functional assays, proteomics, and in vivo models to dissect the role of FERMT2 in modulating GC-GCAF interactions and its contribution to peritoneal dissemination.Results: FERMT2 is highly expressed in CAFs and positively correlates with both CAF infiltration and activation in GC.Functionally, FERMT2 maintains the myofibroblastic phenotype of GCAFs by acting as a competing endogenous RNA (ceRNA) for ZEB2, thereby promoting α-SMA transcription.FERMT2 also drives GCAF-derived secretion of transforming growth factor-beta 1 (TGF-β1), which in turn induces FERMT2 expression in GC cells, enhancing their migration, invasion, and resistance to anoikis.In parallel, tumor-derived FERMT2 upregulates COL6A1 and facilitates its transfer to GCAFs via exosomes, amplifying TGF-β signaling and reinforcing CAF activation.Intracellular COL6A1 sustains the pro-metastatic phenotype of GCAFs.Together, these interactions constitute a TGF-β1/FERMT2/COL6A1 positive feedback loop that fuels tumor-stroma crosstalk and promotes peritoneal dissemination in GC.Conclusion: This study identifies a reciprocal regulatory loop involving FERMT2, TGF-β1, and COL6A1, which promotes tumor-stroma interaction and peritoneal dissemination, suggesting a potential therapeutic target for advanced gastric cancer.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.119895