癌症转移,即,肿瘤细胞从原发肿瘤扩散到远处器官,是绝大多数癌症死亡的原因。在这个过程中,癌细胞通过狭窄的间质空间迁移,横截面比细胞小得多。在这种有限的迁移过程中,癌细胞经历广泛的核变形,核包膜破裂,和DNA损伤。导致限制性迁移诱导的DNA损伤的分子机制仍未完全了解。虽然在一些细胞系中,DNA损伤与核包膜破裂密切相关,我们证明,在其他方面,细胞核的机械变形足以造成DNA损伤,即使在没有核膜破裂的情况下。这种变形引起的DNA损伤,与核包膜破裂引起的DNA损伤不同,主要发生在细胞周期的S/G2期,并与复制叉有关。核变形,由于有限的迁移或外部细胞压缩,增加复制压力,可能是通过增加复制叉的失速,为变形诱导的DNA损伤提供了分子机制。因此,我们发现了一种机械诱导DNA损伤的新机制,将细胞核的机械变形与DNA复制应力联系起来。这种机械诱导的DNA损伤不仅会增加转移癌细胞的基因组不稳定性,而且还会导致在发育过程中经历机械压缩的非迁移细胞和组织的DNA损伤。从而促进肿瘤发生和DNA损伤反应激活。
Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migration-induced DNA damage remain incompletely understood. Although in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that, in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear-envelope-rupture-induced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication stress, possibly by increasing replication fork stalling, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells but could also cause DNA damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.