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

Project description

Mechanical cues in epithelial cell turnover

Understanding the cues that drive cell proliferation and death in different tissues is central for deciphering the mechanisms of carcinogenesis. In the epithelial tissue, mechanical forces seem to control these processes, with stretch activating proliferation and crowding triggering cell death. The scope of the EU-funded PROMIGREX project is to extend these findings and investigate the impact of cell migration on normal and abnormal cell turnover in epithelial tissues. Scientists will determine the role of the stretch-activated Piezo1 protein in cell migration from sites of high division rate alongside the role of mutations in colon cancer. The project's results will disclose important information about epithelial carcinogenesis and potentially unveil new therapeutic targets.

Objective

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.

Coordinator

KING'S COLLEGE LONDON
Net EU contribution
€ 212 933,76
Address
STRAND
WC2R 2LS London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 212 933,76