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

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