Tissue Crowding Induces Caspase-Dependent Competition for Space.
Tissue Crowding Induces Caspase-Dependent Competition for Space.
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DOI：
10.1016/j.cub.2015.12.072
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发表时间：
2016-03-07
期刊：
影响因子：
--
通讯作者：
Moreno E
中科院分区：
文献类型：
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作者：
Levayer R;Dupont C;Moreno E
组织大小的调节需要在单细胞水平上对增殖速率、细胞体积和细胞死亡进行微调。尽管增殖和生长的调节已经被广泛研究，但细胞死亡的贡献及其对组织尺度参数的调节迄今为止还没有被探索。最近，它表明，上皮细胞可以消除活细胞分层的细胞密度的增加作出反应。细胞分层应该独立于半胱天冬酶激活而发生，并被认为是基于分层细胞中连接的逐渐和自发消失。研究果蝇蛹背中线区域细胞的消除，我们发现，与之前的建议相反，Caspase 3激活先于细胞分层，并且是细胞分层所需的。然而，使用粒子图像测速仪，遗传学和激光诱导的扰动，我们证实了局部组织拥挤是必要的，足以驱动细胞消除，细胞消除是独立于已知的健身依赖的竞争途径。因此，在克隆中癌基因Ras的激活足以压缩邻近组织并消除远离克隆几个细胞直径的细胞。以前已经提出机械应力有助于细胞竞争。这些结果提供了第一个实验证据，即拥挤诱导的死亡可能是一种替代模式的超级竞争，即机械超级竞争，独立于已知的健身标志物，可以促进肿瘤生长。半胱天冬酶激活是果蝇蛹背中细胞分层所必需的。半胱天冬酶激活是由局部组织拥挤驱动的。拥挤诱导的死亡在抗凋亡的快速生长克隆附近被激活。显示上皮拥挤通过半胱天冬酶激活和细胞分层驱动随机细胞消除。同样的现象也发生在快速生长的抗凋亡克隆的附近，并可能通过消除邻近细胞而促进肿瘤细胞的扩增。
Regulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied, the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density. Cell delamination was supposed to occur independently of caspase activation and was suggested to be based on a gradual and spontaneous disappearance of junctions in the delaminating cells. Studying the elimination of cells in the midline region of the Drosophila pupal notum, we found that, contrary to what was suggested before, Caspase 3 activation precedes and is required for cell delamination. Yet, using particle image velocimetry, genetics, and laser-induced perturbations, we confirmed that local tissue crowding is necessary and sufficient to drive cell elimination and that cell elimination is independent of known fitness-dependent competition pathways. Accordingly, activation of the oncogene Ras in clones was sufficient to compress the neighboring tissue and eliminate cells up to several cell diameters away from the clones. Mechanical stress has been previously proposed to contribute to cell competition. These results provide the first experimental evidences that crowding-induced death could be an alternative mode of super-competition, namely mechanical super-competition, independent of known fitness markers, that could promote tumor growth. Caspase activation is necessary for cell delamination in the Drosophila pupal notum Caspase activation is driven by local tissue crowding Crowding-induced death is activated near fast-growing clones resistant for apoptosis It is a new mode of super-competition that may promote expansion of tumoral cells Using the Drosophila pupal notum, Levayer et al. show that epithelium crowding drives random cell elimination through caspase activation and cell delamination. The same phenomenon occurs in the neighborhood of fast growing clones resistant for apoptosis and may promote tumoral cell expansion through the elimination of the neighboring cells.