FN1 from cancer-associated fibroblasts orchestrates pancreatic cancer metastasis via integrin-PI3K/AKT signaling.

OBJECTIVE: The metastasis of pancreatic ductal adenocarcinoma (PDAC) is closely linked to the remodeling of cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), though the precise molecular mechanisms remain unclear. This study aims to elucidate the role of CAFs in PDAC metastasis. METHODS: We integrated transcriptomic (GSE183795) and single-cell sequencing data (GSE156405) to screen for core genes associated with PDAC. In vitro co-culture models, functional assays (Transwell migration, Western blotting, qRT-PCR), and clinical data analysis were employed. RESULTS: Multi-omics analysis identified FN1 as a pivotal hub gene in the PI3K pathway, highly expressed in metastatic CAF subsets. In vitro experiments confirmed that FN1 activates the PI3K/AKT pathway through integrin receptors, influencing cell invasion and the immune microenvironment. Combined inhibition of the PI3K/AKT pathway and integrins synergistically suppressed tumor invasion. Clinical data showed that high FN1 expression correlated with shortened patient survival and an immunosuppressive microenvironment (M2 macrophage/Treg cell infiltration). CONCLUSION: FN1 directly drives PDAC metastasis via the integrin-PI3K/AKT axis and indirectly promotes a "cold tumor" microenvironment by recruiting immunosuppressive cells. This dual role of FN1 enhances our understanding of CAFs heterogeneity and offers novel therapeutic strategies for PDAC.