SERPINE1 as a critical CAF-associated gene promotes myCAF phenotype activation and exosome-mediated gastric cancer progression

Purpose Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and are associated with poor prognosis in several cancers. SERPINE1 (serpin family E member 1; also known as plasminogen activator inhibitor-1, PAI-1) is a serine protease inhibitor that regulates extracellular matrix (ECM) remodeling and has been implicated in tumor progression. However, the role of SERPINE1 in CAFs remains unclear. In this study, we identified SERPINE1 as a CAF-associated gene in gastric cancer, investigated its regulatory role in CAFs, and evaluated its impact on gastric cancer (GC) progression Methods We evaluated stomach adenocarcinoma data from The Cancer Genome Atlas and utilized weighted gene co-expression network analysis and related bioinformatics approaches to identify CAF-related genetic drivers. SERPINE1 expression was quantified and modulated to test its impact on CAF proliferation/migration and transforming growth factor (TGF-β)–driven myofibroblastic activation via PI3K-Akt signaling. Additionally, SERPINE1-enriched exosomes from CAFs were characterized and assessed for their effects on tumor cells. Furthermore, we evaluated the impact of CAF-derived SERPINE1-enriched exosomes on gastric cancer progression and MDSC infiltration using subcutaneous xenograft and liver metastasis models in nude mice Results SERPINE1 emerged as a key CAF-related gene in GC showing a significant correlation with unfavorable patient prognosis. In vitro, SERPINE1 was highly expressed in GC-derived CAFs and promoted their proliferation and migration. In addition, SERPINE1 enhanced TGF-β–induced activation of normal fibroblasts into myofibroblastic CAFs (myCAFs) through the PI3K-Akt signaling pathway. Furthermore, CAF-derived SERPINE1-enriched exosomes facilitated gastric cancer progression, supported the maintenance of gastric cancer cell stemness, and promoted MDSC infiltration. Conclusions Our findings highlight the potential of targeting SERPINE1 for suppressing myCAF activation and tumor progression, providing a promising therapeutic strategy for GC.