E-cadherin is the primary mediator of strong cell-cell adhesion between epithelial cells and plays an essential role in the morphogenesis and maintenance of epithelial tissues. E-cadherin adhesion is modulated by multiple biochemical and biophysical cues. The long term goal of the project is to understand how the mechanical regulation of E-cadherin adhesion leads to a cohesive yet dynamic multi-cellular architecture in epithelial tissues. The goal of the proposed project is to uncover how the epithelial cell- specific viscoelastic microenvironment of E-cadherin modulates its adhesion and how E-cadherin- dependent Rho GTPase activity and tension in turn modulate this viscoelasticity. Firstly, E-cadherin is known to be a mechanosensor and resides in a microenvironment formed by the adjoining epithelial cells. However, how epithelial cell-like viscoelastic properties modulate E-cadherin adhesion is not known. Secondly, it is not clear how E-cadherin dependent biochemical signals in turn modulate its microenvironmental viscoelasticity. In particular, the effect of Rho and Rac, known modulators of the actin cytoskeleton, on E-cadherin microenvironment viscoelastic properties is unclear. This effect is essential to understand in order to delineate the role of these Rho GTPases in mediating cell-cell contact formation. Thirdly, E-cadherin adhesions transmit cell-generated as well as external forces imposed on epithelial tissues. How the level of this tension transmitted across cells determines the viscoelastic properties close to cell-cell junctions is unknown. Knowledge of cell viscoelastic properties near cell-cell junctions is important not only to understand E-cadherin mechanobiology, but more generally to also understand cell deformation in response to forces transmitted at cell-cell adhesions. We will use an array of tools including E-cadherin biomimetic substrates with tunable viscoelastic properties similar to epithelial cells, flow assays with such E- cadherin soft substrates, magnetic pulling cytometry and high resolution traction force microscopy in the presence and absence of external stretch, to answer these questions at the sub-cellular, cellular and supra- cellular levels. Results of the proposed project will be crucial in understanding the context-dependent biophysical control of E-cadherin adhesion. Knowledge gained from the project will be essential to better understand the functional basis of the role of E-cadherin in mediating epithelial tissue integrity, mechanical coherence and its dysregulation in disease states like cancer.
The proposed project determines how adhesions that help cells stick to one another in solid tissues may in turn depend on the mechanical properties of cells around the adhesions. Attainment of the aims proposed in the project will enable a better understanding of key events in development as well as what disrupts tissue organization in diseases like cancer.
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