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

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.