Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.
Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.
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DOI：
10.1038/s41556-020-0552-6
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发表时间：
2020-09
影响因子：
21.3
通讯作者：
Friedl P
中科院分区：
文献类型：
--
作者：
Ilina O;Gritsenko PG;Syga S;Lippoldt J;La Porta CAM;Chepizhko O;Grosser S;Vullings M;Bakker GJ;Starruß J;Bult P;Zapperi S;Käs JA;Deutsch A;Friedl P
癌症侵袭和转移的可塑性取决于癌细胞在由钙粘附素介导的细胞-细胞连接控制的集体和单细胞扩散之间切换的能力。在临床样本中，E-钙粘附素表达和E-钙粘附素缺陷的肿瘤共同侵袭和同等转移，暗示了控制细胞间合作和个体化的额外机制。在这里，使用空间定义的器官类型培养，小鼠乳腺肿瘤的活体显微镜和电子计算机模型，我们确定了三维组织边界对细胞密度的调节，以物理控制集体运动，而与细胞-细胞连接的组成和稳定性无关。通过下调E-钙粘附素和p120-连环素的表达来解除黏附连接的调控，导致沿细胞外边界从协调的集体运动转变为非协调的集体运动，而单细胞的逃逸依赖于局部的自由组织空间。这些结果表明，钙粘附素和细胞外基质限制共同决定了无干扰的转变和逐步的上皮流态化，最终走向细胞的个体化。
Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell–cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell–cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in mice and in silico modelling, we identify cell density regulation by three-dimensional tissue boundaries to physically control collective movement irrespective of the composition and stability of cell–cell junctions. Deregulation of adherens junctions by downregulation of E-cadherin and p120-catenin resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas single-cell escape depended on locally free tissue space. These results indicate that cadherins and extracellular matrix confinement cooperate to determine unjamming transitions and stepwise epithelial fluidization towards, ultimately, cell individualization.
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