Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes via distinct mechanotransduction pathways. In breast cancer, increased ECM stiffness promotes epithelial-to-mesenchymal transition (EMT), cell invasion, and metastasis. Here, we identify a mechanosensitive EPHA2/LYN protein complex regulating EMT and metastasis in response to increasing ECM stiffness during tumor progression. High ECM stiffness leads to ligand-independent phosphorylation of ephrin receptor EPHA2, which recruits and activates the LYN kinase. LYN phosphorylates the EMT transcription factor TWIST1 to release TWIST1 from its cytoplasmic anchor G3BP2 to enter the nucleus, thus triggering EMT and invasion. Genetic and pharmacological inhibition of this pathway prevents breast tumor invasion and metastasis in vivo. In human breast cancer samples, activation of this pathway correlates with collagen fiber alignment, a marker of increasing ECM stiffness. Our findings reveal an EPHA2/LYN/TWIST1 mechanotransduction pathway that responds to mechanical signals from the tumor microenvironment to drive EMT, invasion, and metastasis.

来自细胞外基质 (ECM) 的机械线索通过不同的机械转导途径调节各种细胞过程。在乳腺癌中，增加的 ECM 刚度会促进上皮间质转化 (EMT)、细胞侵袭和转移。在这里，我们确定了一种机械敏感性 EPHA2/LYN 蛋白复合物，可调节 EMT 和转移，以响应肿瘤进展过程中增加的 ECM 刚度。高 ECM 刚度导致 ephrin 受体 EPHA2 的配体非依赖性磷酸化，其募集并激活 LYN 激酶。LYN 磷酸化 EMT 转录因子 TWIST1，从其胞质锚 G3BP2 释放 TWIST1 进入细胞核，从而触发 EMT 和侵袭。该途径的遗传和药理学抑制可防止体内乳腺肿瘤侵袭和转移. 在人类乳腺癌样本中，该通路的激活与胶原纤维排列相关，胶原纤维排列是增加 ECM 硬度的标志。我们的研究结果揭示了一个 EPHA2/LYN/TWIST1 机械转导通路，该通路对来自肿瘤微环境的机械信号作出反应，以驱动 EMT、侵袭和转移。