Denais Celine M, Gilbert Rachel M, Isermann Philipp, McGregor Alexandra L, te Lindert Mariska, Weigelin Bettina, Davidson Patricia M, Friedl Peter, Wolf Katarina, Lammerding Jan
Nancy E. and Peter C. Meinig School of Biomedical Engineering and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
Department of Cell Biology, Radboud University Medical Center, Nijmegen, Netherlands.
Science. 2016 Apr 15;352(6283):353-8. doi: 10.1126/science.aad7297. Epub 2016 Mar 24.
During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
在癌症转移过程中，肿瘤细胞通过紧密的间质空间穿透组织，这需要细胞及其细胞核进行广泛的变形。在此，我们研究了哺乳动物肿瘤细胞在体外和体内受限微环境中的迁移情况。核变形导致核膜（NE）完整性的局部丧失，进而导致核质内容物的不受控交换、染色质穿过核膜的疝出以及DNA损伤。核膜破裂的发生率随着细胞受限程度以及核纤层蛋白（在结构上支持细胞核的核膜蛋白）的耗竭而增加。细胞利用运输所需的内体分选复合物III（ESCRT III）机制的组分来恢复核膜完整性。我们的研究结果表明，细胞迁移会给核膜及其内容物带来巨大的物理压力，并且细胞存活需要有效的核膜和DNA损伤修复。
