Integrin-linked kinase tunes cell-cell and cell-matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGF beta 1

Epithelial-mesenchymal transition (EMT) is a morphogenetic process that endows epithelial cells with migratory and invasive potential. Mechanical and chemical signals from the tumor microenvironment can activate the EMT program, thereby permitting cancer cells to invade the surrounding stroma and disseminate to distant organs. Transforming growth factor beta 1 (TGF beta 1) is a potent inducer of EMT that can also induce apoptosis depending on the microenvironmental context. In particular, stiff microenvironments promote EMT while softer ones promote apoptosis. Here, we investigated the molecular signaling downstream of matrix stiffness that regulates the phenotypic switch in response to TGF beta 1 and uncovered a critical role for integrin-linked kinase (ILK). Specifically, depleting ILK from mammary epithelial cells precludes their ability to sense the stiffness of their microenvironment. In response to treatment with TGF beta 1, ILK-depleted cells undergo apoptosis on both soft and stiff substrata. We found that knockdown of ILK decreases focal adhesions and increases cell-cell adhesions, thus shifting the balance from cell-matrix to cell-cell adhesion. High cellmatrix adhesion promotes EMT whereas high cell-cell adhesion promotes apoptosis downstream of TGF beta 1. These results highlight an important role for ILK in controlling cell phenotype by regulating adhesive connections to the local microenvironment.

Automated summary

Epithelial-mesenchymal transition (EMT) is an essential process for cancer cells invasion and dissemination, which is influenced by signals from the tumor microenvironment. This study revealed a critical role of integrin-linked kinase (ILK) in controlling cell phenotype by regulating adhesive connections to the local microenvironment in response to TGF beta 1.