Mechanical regulation of cell migration by Piezo1 and its implications in epithelial cell turnover

ended

Cancers arise in cell types that turnover by proliferation and death at highest rates, likely because these rates become unbalanced. Our group found that mechanical forces control both processes in epithelia: stretch activates proliferation whereas crowding activates cell extrusion and death. However, it was unclear what causes crowding and stretching forces in epithelia. I will investigate if cell migration from sites of proliferation drives the conveyor belt forces that control stretch-induced cell division and crowding-induced death. If so, the rate of cell migration could drive the rate of cell turnover and, hence, the propensity for a tissue to become cancerous. While my host lab has already identified roles for the stretch- activated ion channel Piezo1 in controlling proliferation and extrusion, based on preliminary compelling findings, I will determine if it also controls cell migration from sites of division. To do so, I will use established models in cell culture and mouse gut and develop an in vivo zebrafish gut model for homeostatic epithelial cell turnover. Additionally, I will test if frequent Piezo1 mutations in colon cancer impact cell proliferation, migration, and death. If my hypothesis is correct, I will reveal a new, unexpected role for cell migration in not only normal epithelial cell turnover but also in carcinogenesis. Should Piezo1 act as a central transducer of mechano-chemical coupling, it could provide a new target for therapeutics.