The extracellular matrix dictates ovarian cancer cell migration in an in vivo-derived circulating environment

Abstract

Ovarian cancer (OC) disseminates via ascites and interaction with peritoneal extracellular matrix (ECM). To dissect the crosstalk between ECM and ascites in OC cell migration, we developed an ovarian tumor-on-chip integrating OC tumor spheroids, perfusion-induced shear stress of fluid supplemented with key components of ascites or patient-derived ascites, and biomimetic ECMs mimicking either early-stage basement membrane or late-stage connective tissues. We evaluated the individual and combined effects of two key ascitic components, fibronectin and TGF-{beta}, and compared these results with the perfusion of patient ascites. Results showed that cell migration, morphology, and epithelial-to-mesenchymal transition (EMT) markers such as the reorganization of vimentin cytoskeleton depend strongly on ECM composition, regardless of biochemical cues. Fibronectin and TGF-{beta} synergistically enhanced migration and EMT signatures, especially on basement membrane-rich ECM. Patient ascites further promoted migration but did not override ECM-driven migration patterns. Our findings show that clinical ascites perfusion exemplifies the ECM-dependence of cancer cell migration. This highlights that ECM protein composition is a dominant regulator of OC cell migration, providing key insights for in vitro tumor modeling and therapeutic strategies targeting the metastatic microenvironment.