Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells.
Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells.
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DOI：
10.1083/jcb.201704102
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发表时间：
2018-01-02
期刊：
影响因子：
--
通讯作者：
Godinho SA
中科院分区：
文献类型：
--
作者：
Rhys AD;Monteiro P;Smith C;Vaghela M;Arnandis T;Kato T;Leitinger B;Sahai E;McAinsh A;Charras G;Godinho SA
中心体聚集对于含有额外中心体的细胞的存活是必不可少的。Rhys等人表明，中心体成簇是一个两步机制，其中由E-钙粘蛋白丢失驱动的皮质收缩性增加限制了中心体运动，促进了HSET介导的成簇。中心体扩增是人类肿瘤的常见特征。为了生存，癌细胞在有丝分裂期间聚集额外的中心体，避免多极分裂的有害影响。然而，目前还不清楚聚类是否需要适应或固有的所有细胞。在这里，我们表明，细胞有不同的能力集群额外的中心体。上皮细胞在成簇方面是天生低效的，即使在存在HSET/KIFC 1的情况下也是如此，HSET/KIFC 1对于促进成簇是必要的但不足以促进成簇。E-钙粘蛋白的存在通过导致多极分裂的信号级联降低有丝分裂期间的皮质收缩性，并且其敲除促进具有多个中心体的细胞的聚集和存活。皮质收缩性将中心体运动限制在HSET/KIFC 1发挥其功能所需的最小距离，突出了中心体聚集的双相模型。在乳腺癌细胞系中，中心体扩增水平的增加伴随着E-钙粘蛋白的有效聚集和丢失，表明这是癌症中中心体扩增的重要适应机制。
Centrosome clustering is essential for the survival of cells containing supernumerary centrosomes. Rhys et al. show that centrosome clustering is a two-step mechanism in which increased cortical contractility, driven by loss of E-cadherin, restricts centrosome movement, facilitating HSET-mediated clustering. Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes. Cortical contractility restricts centrosome movement at a minimal distance required for HSET/KIFC1 to exert its function, highlighting a biphasic model for centrosome clustering. In breast cancer cell lines, increased levels of centrosome amplification are accompanied by efficient clustering and loss of E-cadherin, indicating that this is an important adaptation mechanism to centrosome amplification in cancer.
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