Macrophage-derived FN1 promotes peritoneal cavity metastasis of gastric cancer by inhibiting the Hippo signaling pathway via SDC4

Gastric cancer (GC) is a prevalent malignant tumor worldwide. Peritoneal cavity metastasis is recognized as a critical clinical feature of late-stage GC. Fibronectin 1 (FN1) is closely associated with the development and progression of various cancers. This study aimed to investigate the functions of FN1 and the underlying mechanisms in peritoneal cavity metastasis of GC. A bioinformatics reanalysis of the single-cell sequencing dataset GSE140182 was performed to explore the cellular signature in malignant ascites. Cell communication analysis was performed to identify the cell communication between macrophages and tumor cells. GC cells were cultured with supernatant from FN1-overexpressing macrophages to investigate the effects and potential mechanism of FN1 action on GC cells by Western blot (WB) assay, MTT assay, migration and invasion assay, clone formation assay, cell adhesion assay, and functional rescue experiments. To further validate the impact of FN1 on GC and its peritoneal cavity metastasis were carried out in vivo experiments. Cellular communication between macrophages and GC cells was mediated by FN1-SDC4. Overexpression of macrophage-derived FN1 facilitated the malignant phenotypes of GC cells and the peritoneal cavity metastasis of GC in vivo. Mechanistically, macrophage-derived FN1 inhibited the Hippo signaling pathway by enhancing the expression of SDC4 in GC cells. Knockdown of SDC4 reversed the tumor-promoting effects induced by macrophage-derived FN1. Our study revealed that macrophage-derived FN1 inhibited the Hippo signaling pathway by upregulating the expression of SDC4 in GC cells, thereby promoting peritoneal cavity metastasis of GC.