Extracellular matrix viscoelasticity regulates TGFß1-induced epithelial-mesenchymal transition and apoptosis via integrin linked kinase.

ABSTRACT

Transforming growth factor (TGF)-ß1 is a multifunctional cytokine that plays important roles in health and disease. Previous studies have revealed that TGFß1 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 TGFß1 remains unknown. Here, we synthesized polyacrylamide hydrogels that mimic the viscoelastic properties of breast tumor tissue. We found that increasing matrix viscous dissipation reduces TGFß1-induced cell spreading, F-actin stress fiber formation, and EMT-associated gene expression changes, and promotes TGFß1-induced apoptosis in mammary epithelial cells. Furthermore, TGFß1-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 TGFß1-induced EMT and reduces apoptosis in cells cultured on viscoelastic substrata, suggesting that ILK plays an important role in regulating cell fate downstream of TGFß1 in response to matrix viscoelasticity.