FERMT2 drives anoikis resistance and peritoneal metastasis by enhancing extracellular matrix deposition in gastric cancer

Abstract Peritoneal metastasis is a critical step in the progression of gastric cancer (GC), yet its underlying mechanisms remain poorly understood. Here, we identify FERMT2, a member of the Kindlin protein family, as a key regulator of anoikis resistance (AR) and peritoneal metastasis in GC. FERMT2 expression increases in a suspension-time-dependent manner and is associated with higher pathological grade, advanced clinical stage, and poorer prognosis. Functional studies in vitro and in vivo demonstrate that FERMT2 promotes AR and facilitates peritoneal metastasis. Mechanistically, FERMT2 suppresses the ubiquitination of SOX2, thereby enhancing its stability and up-regulating FN1 transcription. Furthermore, we report that TGFβ-RI expression also increases in a suspension-time-dependent manner, forming a positive feedback loop with FERMT2 via TGFβ-1/TGFβ-RI signaling. This feedback loop drives extracellular fibronectin matrix deposition, strengthens cell–matrix interactions, and supports AR. These findings establish FERMT2 as a pivotal mediator of peritoneal metastasis in GC, offering insights into its potential as a therapeutic target.