Calcium signaling induces a partial EMT
Calcium signaling induces a partial EMT
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DOI：
10.15252/embr.202051872
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发表时间：
2021-07-29
期刊：
影响因子：
7.7
通讯作者：
Stanger, Ben Z.
中科院分区：
文献类型：
--
作者：
Norgard, Robert J.;Pitarresi, Jason R.;Stanger, Ben Z.
上皮可塑性或上皮-间充质转化（EMT）是细胞可塑性的公认形式，其赋予肿瘤细胞侵袭性并改变其对各种药剂的敏感性，因此代表癌症治疗的主要挑战。越来越多的人认为，癌细胞沿着一个连续的混合上皮-间充质（E-M）状态存在，并且表现出这种部分EMT（P-EMT）状态的细胞比以任一极端（E或M）为特征的细胞具有更大的转移能力。我们最近描述了一种在体内运行的P-EMT程序，通过该程序，癌细胞通过翻译后程序失去其上皮状态。在这里，我们研究了潜在的机制，并报告说，长期的钙信号诱导P-EMT的特点是内化的膜相关的E-钙粘蛋白（ECAD）和其他上皮蛋白，以及增加细胞迁移和侵袭。通过G α q相关的G蛋白偶联受体（GPCR）的信号传导概括了这些作用，其通过钙调蛋白-Camk 2b信号传导的下游激活起作用。这些结果暗示钙信号传导是癌细胞获得混合/部分上皮-间充质状态的触发器。
Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through G alpha q-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.