Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation.
Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation.
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DOI：
10.1016/j.cub.2023.05.061
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发表时间：
2023-07-10
期刊：
影响因子：
--
通讯作者：
Matthews HK
中科院分区：
文献类型：
--
作者：
Ganguli S;Wyatt T;Nyga A;Lawson RH;Meyer T;Baum B;Matthews HK
致癌Ras已被证明可以通过增加有丝分裂过程中产生的力量来改变癌细胞的分裂方式。通过这种方式，RasV12使癌细胞能够在比正常细胞更广泛的机械环境中分裂。在这里，我们通过显示RasV12表达改变细胞有丝分裂后的形状、分裂方向和再复制动力学，进一步确定了致癌Ras-ERK信号在分裂中的作用。许多这些影响似乎是由于RasV12信号对肌动球蛋白收缩性的影响，因为RasV12诱导了通常引导纺锤体定位和提供间期细胞形状记忆的收缩纤维的切断。为了支持这一观点，RasV12表型可以通过抑制肌动球蛋白收缩性而逆转，并且可以通过有丝分裂期间细胞-底物粘附的丧失来模拟。最后，我们发现，在二维上皮单层和三维球体中培养的细胞中，RasV12的激活也会扰乱分裂方向。因此，致癌Ras-ERK信号的诱导导致分裂方向的快速变化，以及RasV12对细胞生长和细胞周期进展的影响，可能会破坏上皮组织并促进癌症的传播。
Oncogenic Ras has been shown to change the way cancer cells divide by increasing the forces generated during mitotic rounding. In this way, RasV12 enables cancer cells to divide across a wider range of mechanical environments than normal cells. Here, we identify a further role for oncogenic Ras-ERK signaling in division by showing that RasV12 expression alters the shape, division orientation, and respreading dynamics of cells as they exit mitosis. Many of these effects appear to result from the impact of RasV12 signaling on actomyosin contractility, because RasV12 induces the severing of retraction fibers that normally guide spindle positioning and provide a memory of the interphase cell shape. In support of this idea, the RasV12 phenotype is reversed by inhibition of actomyosin contractility and can be mimicked by the loss of cell-substrate adhesion during mitosis. Finally, we show that RasV12 activation also perturbs division orientation in cells cultured in 2D epithelial monolayers and 3D spheroids. Thus, the induction of oncogenic Ras-ERK signaling leads to rapid changes in division orientation that, along with the effects of RasV12 on cell growth and cell-cycle progression, are likely to disrupt epithelial tissue organization and contribute to cancer dissemination.
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