Extracellular matrix viscoelasticity regulates TGFβ1-induced epithelial-mesenchymal transition and apoptosis via integrin linked kinase

Transforming growth factor (TGF)-beta 1 is a multifunctional cytokine that plays important roles in health and disease. Previous studies have revealed that TGF beta 1 activation, signaling, and downstream cell responses including epithelial-mesenchymal transition (EMT) and apoptosis are regulated by the elasticity or stiffness of the extracellular matrix. However, tissues within the body are not purely elastic, rather they are viscoelastic. How matrix viscoelasticity impacts cell fate decisions downstream of TGF beta 1 remains unknown. Here, we synthesized polyacrylamide hydrogels that mimic the viscoelastic properties of breast tumor tissue. We found that increasing matrix viscous dissipation reduces TGF beta 1-induced cell spreading, F-actin stress fiber formation, and EMT-associated gene expression changes, and promotes TGF beta 1-induced apoptosis in mammary epithelial cells. Furthermore, TGF beta 1-induced expression of integrin linked kinase (ILK) and colocalization of ILK with vinculin at cell adhesions is attenuated in mammary epithelial cells cultured on viscoelastic substrata in comparison to cells cultured on nearly elastic substrata. Overexpression of ILK promotes TGF beta 1-induced EMT and reduces apoptosis in cells cultured on viscoelastic substrata, suggesting that ILK plays an important role in regulating cell fate downstream of TGF beta 1 in response to matrix viscoelasticity.