During amoeboidal migration, cancer cells migrate in a protease-independent manner by squeezing through pre-existing gaps in the extracellular matrix (ECM). However, the extent to which cells alter their physical properties in order to sustain this mode of migration remains unclear. Here, we address this question by documenting biophysical changes in the properties of highly invasive MDA-MB-231 and HT-1080 cells upon inhibition of pericellular proteolysis. Remarkably, treatment with the broad spectrum MMP inhibitor GM6001 not only induces cell rounding and loss of actomyosin contractility, but also induces nuclear softening via increased phosphorylation of the nuclear membrane protein lamin A/C. Though nuclear softening is necessary for sustaining migration through sub-nuclear sized transwell pores, it is not sufficient. In addition, baseline levels of contractility mediating pore entry and peri-nuclear actin inside the pores mediating pore migration are also required. Taken together, our results suggest that protease-independent migration through sub-nuclear sized pre-existing tracks is enabled by deformation of a softened nucleus by contractility and the peri-nuclear actin network.

中文翻译：

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核软化对于不依赖蛋白酶的迁移至关重要。

在变形虫的迁移过程中，癌细胞通过挤压细胞外基质（ECM）中预先存在的缺口以蛋白酶独立的方式迁移。然而，细胞改变其物理性质以维持这种迁移模式的程度仍不清楚。在这里，我们通过记录抑制细胞周围蛋白水解的高侵入性MDA-MB-231和HT-1080细胞特性的生物物理变化来解决这个问题。值得注意的是，用广谱MMP抑制剂GM6001进行的处理不仅诱导细胞圆化和放线肌球蛋白收缩力的丧失，而且还通过增加核膜蛋白层粘连蛋白A / C的磷酸化来诱导核软化。尽管核软化对于维持通过亚核大小的井间孔的迁移是必要的，但这还不够。此外，还需要介导孔进入的收缩力的基线水平和介导孔迁移的孔内核周肌动蛋白的基线水平。两者合计，我们的结果表明，通过收缩力和核周肌动蛋白网络使软化的核变形，可以通过亚核大小的既有轨道进行蛋白酶非依赖性迁移。