Biomedical Engineering Department, Cornell University, Ithaca, NY, United States.
Lab Chip. 2013 Feb 7;13(3):340-8. doi: 10.1039/c2lc41117b.
Mechanical boundaries that define and regulate biological processes, such as cell-cell junctions and dense extracellular matrix networks, exist throughout the physiological landscape. During metastasis, cancer cells are able to invade across these barriers and spread to distant tissues. While transgressing boundaries is a necessary step for distal colonies to form, little is known about interface effects on cell behavior during invasion. Here we introduce a device and metric to assess cell transition effects across mechanical barriers. Using MDA-MB-231 cells, a highly metastatic breast adenocarcinoma cell line, our results demonstrate that dimensional modulation in confined spaces with mechanical barriers smaller than the cell nucleus can induce distinct invasion phases and elongated morphological states. Further investigations on the impact of microtubule stabilization and drug resistance reveal that taxol-treated cells have reduced ability in invading across tight spaces and lose their super-diffusive migratory state and taxol-resistant cells exhibit asymmetric cell division at barrier interfaces. These results illustrate that subnucleus-scaled confinement modulation can play a distinctive role in inducing behavioral responses in invading cells and can help reveal the mechanical elements of non-proteolytic invasion.
存在于整个生理环境中的机械边界可以定义和调节生物过程，例如细胞-细胞连接和致密细胞外基质网络。在转移过程中，癌细胞能够穿过这些屏障并扩散到远处的组织。虽然跨越边界是形成远处集落的必要步骤，但对于界面效应对细胞入侵过程中行为的影响知之甚少。在这里，我们引入了一种设备和度量标准来评估细胞在穿过机械屏障时的过渡效应。使用 MDA-MB-231 细胞，一种高度转移性的乳腺腺癌细胞系，我们的结果表明，在机械屏障小于细胞核的受限空间中进行尺寸调制可以诱导不同的入侵阶段和拉长的形态状态。进一步研究微管稳定性和耐药性的影响表明，紫杉醇处理的细胞在穿过紧密空间时的入侵能力降低，并且失去了超扩散迁移状态，而紫杉醇耐药细胞在屏障界面处表现出不对称细胞分裂。这些结果表明，亚核尺度的限制调制可以在诱导入侵细胞的行为反应方面发挥独特的作用，并有助于揭示非蛋白水解入侵的力学要素。
