Mismatch in Mechanical and Adhesive Properties Induces Pulsating Cancer Cell Migration in Epithelial Monolayer
Mismatch in Mechanical and Adhesive Properties Induces Pulsating Cancer Cell Migration in Epithelial Monolayer
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DOI：
10.1016/j.bpj.2012.05.005
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发表时间：
2012-06-20
影响因子：
3.4
通讯作者：
Wirtz, Denis
中科院分区：
文献类型：
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作者：
Lee, Meng-Horng;Wu, Pei-Hsun;Wirtz, Denis
癌细胞的力学和粘附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硬度和粘附性对癌细胞在上皮样细胞单层中迁移的功能后果。使用体外共培养系统和活细胞成像，我们发现，与单个细胞或单层癌细胞相比，周围僵硬的未转化细胞显著提高了单个机械柔软的乳腺癌细胞的生长速度。软性肿瘤细胞经历一种不同于传统间充质和阿米巴样迁移的脉动迁移模式，在这种模式下，长期缓慢的随机迁移与极快的定向迁移的短期迁移交织在一起，而周围的僵硬细胞几乎没有净迁移。这种突发性迁移是由肌球蛋白II介导的癌细胞软核的间歇性变形引起的，这种变形是由周围未转化细胞的硬核短暂拥挤引起的，其运动直接依赖于钙粘附素介导的正常细胞和癌细胞之间的不匹配黏附以及正常细胞基于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未转化细胞之间的机械和粘附性不匹配可以触发增强的脉动迁移。这些结果揭示了僵硬的上皮细胞在癌症扩散的早期阶段中与单个癌细胞相邻的作用。
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 alpha-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.