MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
Dev Cell. 2020 Mar 9;52(5):563-573.e3. doi: 10.1016/j.devcel.2020.01.004. Epub 2020 Feb 6.
To divide in a tissue, both normal and cancer cells become spherical and mechanically stiffen as they enter mitosis. We investigated the effect of oncogene activation on this process in normal epithelial cells. We found that short-term induction of oncogenic Ras activates downstream mitogen-activated protein kinase (MEK-ERK) signaling to alter cell mechanics and enhance mitotic rounding, so that Ras-expressing cells are softer in interphase but stiffen more upon entry into mitosis. These Ras-dependent changes allow cells to round up and divide faithfully when confined underneath a stiff hydrogel, conditions in which normal cells and cells with reduced levels of Ras-ERK signaling suffer multiple spindle assembly and chromosome segregation errors. Thus, by promoting cell rounding and stiffening in mitosis, oncogenic Ras enables cells to proliferate under conditions of mechanical confinement like those experienced by cells in crowded tumors.
在组织中分裂时，正常细胞和癌细胞都会变成球形，并在进入有丝分裂时变得机械僵硬。我们研究了致癌基因激活对正常上皮细胞中这一过程的影响。我们发现，短期诱导致癌 Ras 会激活下游有丝分裂原激活的蛋白激酶（MEK-ERK）信号转导，从而改变细胞力学特性并增强有丝分裂时的细胞变圆，因此 Ras 表达的细胞在细胞间期中更软，但在进入有丝分裂时会变得更硬。这些 Ras 依赖性变化使细胞能够在坚硬的水凝胶下可靠地变圆和分裂，在这种条件下，正常细胞和 Ras-ERK 信号通路水平降低的细胞会遭受多个纺锤体组装和染色体分离错误。因此，通过促进有丝分裂时的细胞变圆和变硬，致癌 Ras 使细胞能够在机械限制条件下增殖，就像在拥挤的肿瘤中细胞所经历的那样。
