Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, USA.
Biophys J. 2012 Jun 20;102(12):2731-41. doi: 10.1016/j.bpj.2012.05.005. Epub 2012 Jun 19.
The mechanical and adhesive properties of cancer cells significantly change during tumor progression. Here we assess the functional consequences of mismatched stiffness and adhesive properties between neighboring normal cells on cancer cell migration in an epithelial-like cell monolayer. Using an in vitro coculture system and live-cell imaging, we find that the speed of single, mechanically soft breast carcinoma cells is dramatically enhanced by surrounding stiff nontransformed cells compared with single cells or a monolayer of carcinoma cells. Soft tumor cells undergo a mode of pulsating migration that is distinct from conventional mesenchymal and amoeboid migration, whereby long-lived episodes of slow, random migration are interlaced with short-lived episodes of extremely fast, directed migration, whereas the surrounding stiff cells show little net migration. This bursty migration is induced by the intermittent, myosin II-mediated deformation of the soft nucleus of the cancer cell, which is induced by the transient crowding of the stiff nuclei of the surrounding nontransformed cells, whose movements depend directly on the cadherin-mediated mismatched adhesion between normal and cancer cells as well as α-catenin-based intercellular adhesion of the normal cells. These results suggest that a mechanical and adhesive mismatch between transformed and nontransformed cells in a cell monolayer can trigger enhanced pulsating migration. These results shed light on the role of stiff epithelial cells that neighbor individual cancer cells in early steps of cancer dissemination.
癌细胞的力学和黏附特性在肿瘤进展过程中会发生显著变化。在这里，我们评估了相邻正常细胞之间不匹配的刚度和黏附特性对上皮样细胞单层中癌细胞迁移的功能影响。通过体外共培养系统和活细胞成像，我们发现与单个癌细胞或单层癌细胞相比，周围的刚性非转化细胞会显著增强单个力学上柔软的乳腺癌细胞的迁移速度。柔软的肿瘤细胞经历了一种不同于传统的间质和阿米巴样迁移的脉动式迁移模式，其中长时间的缓慢、随机迁移与短时间的极快、定向迁移交错，而周围的刚性细胞几乎没有净迁移。这种突发式迁移是由柔软的癌细胞的细胞核间歇性、肌球蛋白 II 介导的变形引起的，这种变形是由周围非转化细胞的刚性细胞核的短暂拥挤引起的，这些细胞的运动直接依赖于正常细胞和癌细胞之间的钙黏蛋白介导的不匹配黏附以及正常细胞之间基于α-连环蛋白的细胞间黏附。这些结果表明，细胞单层中转化细胞和非转化细胞之间的力学和黏附不匹配可以触发增强的脉动式迁移。这些结果揭示了硬细胞在上皮细胞层中紧邻单个癌细胞的早期扩散步骤中所起的作用。
