Ascitic Shear Stress Activates GPCRs and Downregulates Mucin 15 to Promote Ovarian Cancer Malignancy

Abstract

The accumulation of ascites in patients with ovarian cancer increases their risk of transcoelomic metastasis. Although common routes of peritoneal dissemination are known to follow distinct paths of circulating ascites, the mechanisms that initiate these currents and subsequent fluid shear stresses are not well understood. Here we developed a patient-based, boundary driven computational fluid dynamics model to predict an upper range of fluid shear stress generated by the accumulation of ascites. We show that ovarian cancer cells exposed to ascitic shear stresses display heightened G protein-coupled receptor mechanosignaling and the induction of an epithelial to mesenchymal-like transition through p38α mitogen-activated protein kinase and mucin 15 modulation. An emergent immunomodulatory secretome and endoplasmic reticulum stress activation is also present in shear stimulated cancer cells, positioning elevated shear stress as a protumoural signal. Together, these findings suggest maintenance strategies for overcoming mechanotransduction mediated metastasis within the peritoneal cavity.