Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Nat Cell Biol. 2019 Feb;21(2):251-262. doi: 10.1038/s41556-018-0268-z. Epub 2019 Jan 21.
Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms. We show that the EMT transcription factor Snail elicits collective migration in squamous cell carcinoma by inducing the expression of a tight junctional protein, claudin-11. Mechanistically, tyrosine-phosphorylated claudin-11 activates Src, which suppresses RhoA activity at intercellular junctions through p190RhoGAP, maintaining stable cell-cell contacts. In head and neck cancer patients, the Snail-claudin-11 axis prompts the formation of circulating tumour cell clusters, which correlate with tumour progression. Overexpression of snail correlates with increased claudin-11, and both are associated with a worse outcome. This finding extends the current understanding of EMT-mediated cellular migration via a non-individual type of movement to prompt cancer progression.
上皮-间充质转化 (EMT) 是癌症扩散的关键机制。然而，在临床样本中，很难检测到 EMT 调控的单个癌细胞侵袭。新出现的证据表明，EMT 与集体细胞迁移和侵袭有关，但具体机制尚不清楚。我们发现 EMT 转录因子 Snail 通过诱导紧密连接蛋白 claudin-11 的表达引发鳞状细胞癌的集体迁移。在机制上，酪氨酸磷酸化的 Claudin-11 激活了Src，Src 通过 p190RhoGAP 抑制细胞间连接的 RhoA 活性，从而维持稳定的细胞-细胞接触。在头颈部癌症患者中，Snail-claudin-11 轴促使循环肿瘤细胞簇的形成，这与肿瘤进展相关。snail 的过表达与 claudin-11 的增加相关，两者都与预后不良相关。这一发现扩展了 EMT 介导的细胞迁移的现有认识，即通过非个体类型的运动来促进癌症进展。
