Epithelial Cell-Like Elasticity Modulates Actin-Dependent E-Cadherin Adhesion Organization

[Image: see text] E-cadherin adhesions are essential for cell-to-cell cohesion and mechanical coupling between epithelial cells and reside in a microenvironment that comprises the adjoining epithelial cells. While E-cadherin has been shown to be a mechanosensor, it is unknown if E-cadherin adhesions can differentially sense stiffness within the range of that of epithelial cells. A survey of literature shows that epithelial cells’ Young’s moduli of elasticity lie predominantly in the sub-kPa to few-kPa range, with cancer cells often being softer than noncancerous ones. Here, we devised oriented E-cadherin-coated soft silicone substrates with sub-kPa or few-kPa elasticity but with similar viscous moduli and found that E-cadherin adhesions differentially organize depending on the magnitude of epithelial cell-like elasticity. Our results show that the actin cytoskeleton organizes E-cadherin adhesions in two ways—by supporting irregularly shaped adhesions at localized regions of high actin density and linear shaped adhesions at the end of linear actin bundles. Linearly shaped E-cadherin adhesions associated with radially oriented actin—but not irregularly shaped E-cadherin adhesions associated with circumferential actin foci—were much more numerous on 2.4 kPa E-cadherin substrates compared to 0.3 kPa E-cadherin substrates. However, the total amount of E-cadherin in both types of adhesions taken together was similar on the 0.3 and 2.4 kPa E-cadherin substrates across many cells. Our results show how the distribution of E-cadherin adhesions, supported by actin density and architecture, is modulated by epithelial cell-like elasticity and have significant implications for disease states like carcinomas characterized by altered epithelial cell elasticity.