Stopping transformed cancer cell growth by rigidity sensing
Stopping transformed cancer cell growth by rigidity sensing
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DOI：
10.1038/s41563-019-0507-0
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发表时间：
2020-02-01
期刊：
影响因子：
41.2
通讯作者：
Sheetz, Michael P.
中科院分区：
文献类型：
--
作者：
Yang, Bo;Wolfenson, Haguy;Sheetz, Michael P.
癌细胞的一个共同特征是蛋白激酶和生化信号通路的改变，使其能够在软基质上转化生长，而细胞骨架蛋白的改变被认为是次要问题。然而，我们在这里报道，来自不同组织的癌细胞可以通过机械感觉模块的缺失或存在分别在转化生长状态和刚性依赖生长状态之间切换。在来自不同组织的不同癌细胞系中，与来自相同组织的正常细胞相比，细胞对僵硬的感觉收缩要少十倍以上。恢复细胞骨架蛋白的正常水平，包括原肌球蛋白，恢复僵硬感觉和依赖僵硬的生长。包括肌球蛋白IIA在内的其他刚性感受器蛋白的进一步耗尽，恢复了转化的生长并阻止了感觉。此外，恢复对癌细胞的刚性感知抑制了肿瘤的形成并改变了表达模式。因此，由于细胞骨架蛋白水平的改变，刚性传感模块的耗尽使得癌细胞能够在柔软的表面上生长，这是癌症进展的一个促成因素。由于特定的细胞骨架传感蛋白的改变，一系列癌细胞类型被证明缺乏刚性传感，这种传感能力可以被传感蛋白从转化为刚性依赖的生长状态，导致收缩和粘附性的恢复。
A common feature of cancer cells is the alteration of kinases and biochemical signalling pathways enabling transformed growth on soft matrices, whereas cytoskeletal protein alterations are thought to be a secondary issue. However, we report here that cancer cells from different tissues can be toggled between transformed and rigidity-dependent growth states by the absence or presence of mechanosensory modules, respectively. In various cancer lines from different tissues, cells had over tenfold fewer rigidity-sensing contractions compared with normal cells from the same tissues. Restoring normal levels of cytoskeletal proteins, including tropomyosins, restored rigidity sensing and rigidity-dependent growth. Further depletion of other rigidity sensor proteins, including myosin IIA, restored transformed growth and blocked sensing. In addition, restoration of rigidity sensing to cancer cells inhibited tumour formation and changed expression patterns. Thus, the depletion of rigidity-sensing modules through alterations in cytoskeletal protein levels enables cancer cell growth on soft surfaces, which is an enabling factor for cancer progression.A range of cancer cell types are shown to lack rigidity-sensing due to alteration in specific cytoskeletal sensor proteins and this sensing ability can be reversed from a transformed to a rigidity-dependent growth state by the sensor proteins, resulting in restoration of contractility and adhesion.