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 β1 (TGFβ1) 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 TGFβ1, 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 TGFβ1, 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 cell-matrix adhesion promotes EMT whereas high cell-cell adhesion promotes apoptosis downstream of TGFβ1. These results highlight an important role for ILK in controlling cell phenotype by regulating adhesive connections to the local microenvironment.

上皮间质转化 (EMT) 是一种形态发生过程，赋予上皮细胞迁移和侵袭潜力。来自肿瘤微环境的机械和化学信号可以激活 EMT 程序，从而允许癌细胞侵入周围的基质并传播到远处的器官。转化生长因子 β1 (TGFβ1) 是一种有效的 EMT 诱导剂，根据微环境也可以诱导细胞凋亡。特别是，僵硬的微环境促进 EMT，而较软的微环境促进细胞凋亡。在这里，我们研究了基质刚度下游的分子信号传导，该信号调节响应 TGFβ1 的表型转换，并发现了整合素相关激酶 (ILK) 的关键作用。具体来说，从乳腺上皮细胞中消耗 ILK 阻止了它们感知微环境僵硬的能力。作为对 TGFβ1 处理的响应，ILK 耗尽的细胞在软质和硬质基质上均发生细胞凋亡。我们发现 ILK 的敲低会减少粘着斑并增加细胞间粘附，从而将平衡从细胞基质转移到细胞间粘附。高细胞基质粘附促进 EMT，而高细胞粘附促进 TGFβ1 下游的细胞凋亡。这些结果突出了 ILK 通过调节与局部微环境的粘附连接来控制细胞表型的重要作用。我们发现 ILK 的敲低会减少粘着斑并增加细胞间粘附，从而将平衡从细胞基质转移到细胞间粘附。高细胞基质粘附促进 EMT，而高细胞粘附促进 TGFβ1 下游的细胞凋亡。这些结果突出了 ILK 通过调节与局部微环境的粘附连接来控制细胞表型的重要作用。我们发现 ILK 的敲低会减少粘着斑并增加细胞间粘附，从而将平衡从细胞基质转移到细胞间粘附。高细胞基质粘附促进 EMT，而高细胞粘附促进 TGFβ1 下游的细胞凋亡。这些结果突出了 ILK 通过调节与局部微环境的粘附连接来控制细胞表型的重要作用。