Department of Molecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, Spain.
Department of Biochemistry and Molecular Biology, University of the Basque Country, Leioa, Spain.
Cell Mol Life Sci. 2023 Oct 6;80(11):316. doi: 10.1007/s00018-023-04968-5.
Nuclear deformability plays a critical role in cell migration. During this process, the remodeling of internal components of the nucleus has a direct impact on DNA damage and cell behavior; however, how persistent migration promotes nuclear changes leading to phenotypical and functional consequences remains poorly understood. Here, we described that the persistent migration through physical barriers was sufficient to promote permanent modifications in migratory-altered cells. We found that derived cells from confined migration showed changes in lamin B1 localization, cell morphology and transcription. Further analysis confirmed that migratory-altered cells showed functional differences in DNA repair, cell response to chemotherapy and cell migration in vivo homing experiments. Experimental modulation of actin polymerization affected the redistribution of lamin B1, and the basal levels of DNA damage in migratory-altered cells. Finally, since major nuclear changes were present in migratory-altered cells, we applied a multidisciplinary biochemical and biophysical approach to identify that confined conditions promoted a different biomechanical response of the nucleus in migratory-altered cells. Our observations suggest that mechanical compression during persistent cell migration has a role in stable nuclear and genomic alterations that might handle the genetic instability and cellular heterogeneity in aging diseases and cancer.
核变形在细胞迁移中起着关键作用。在这个过程中，核内部成分的重塑直接影响 DNA 损伤和细胞行为；然而，持续的迁移如何促进导致表型和功能后果的核变化仍知之甚少。在这里，我们描述了通过物理障碍的持续迁移足以促进迁移改变细胞的永久性改变。我们发现，来源于受限迁移的细胞表现出核纤层蛋白 B1 定位、细胞形态和转录的变化。进一步的分析证实，迁移改变的细胞在 DNA 修复、化疗细胞反应和体内归巢实验中的细胞迁移方面表现出功能差异。肌动蛋白聚合的实验调节影响核纤层蛋白 B1 的重新分布，以及迁移改变细胞中的基础水平 DNA 损伤。最后，由于迁移改变的细胞中存在主要的核变化，我们应用多学科的生化和生物物理方法来确定受限条件促进了迁移改变细胞中核的不同生物力学反应。我们的观察表明，持续细胞迁移过程中的机械压缩在稳定的核和基因组改变中起作用，这些改变可能处理衰老疾病和癌症中的遗传不稳定性和细胞异质性。
