MFAP2 secreted by TGF-β1-induced cancer-associated fibroblast cells promotes gastric cancer peritoneal metastasis through Src-STAT3-PTK7 axis.

Peritoneal metastasis is the leading risk factor for gastric cancer (GC). However, the mechanism of gastric cancer peritoneal metastasis (GCPM) is still unclear. GCPM depends not only on the "seeds" of tumor cells but also on the "soil" of the peritoneal microenvironment. This study aimed to analyze the changes in the peritoneal tissue microenvironment of nine patients with early-stage GC, advanced-stage GC, and GCPM using single-cell transcriptome sequencing. It found that the number of microfiber-associated protein 2 (MFAP2)-positive cancer-associated fibroblasts (CAFs) gradually increased with tumor progression and was associated with poor prognosis of GC during GCPM progression. Mechanistically, GC cells secreted transforming growth factor-β1 (TGF-β1) to stimulate the entry of Smad4 into the nucleus. This promoted the transcription of MFAP2 in peritoneal mesothelial cells and led to mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells into CAFs, thereby altering the peritoneal microenvironment and facilitating the colonization of GC cells on the peritoneum. Moreover, MFAP2 secreted by CAFs bound to the integrin αVβ3 receptor on the surface of GC cells, activating the Src-STAT3 signaling pathway and upregulating the expression of protein tyrosine kinase 7 (PTK7) in GC cells. PTK7 accumulated intracellular β-catenin and facilitated its nuclear entry, activating transcription of downstream target genes to enhance the invasion and adhesion of GC cells, thereby promoting GCPM progression. Our findings provide insights into how changes in the peritoneal microenvironment promote the peritoneal metastasis of GC, thus providing new molecular targets for personalized treatment and prognostic evaluation in clinical practice.