Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement.
Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement.
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DOI：
10.1126/sciadv.abq6480
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发表时间：
2023-01-13
期刊：
影响因子：
13.6
通讯作者：
Konstantopoulos, Konstantinos
中科院分区：
文献类型：
--
作者：
Law, Robert A.;Kiepas, Alexander;Desta, Habben E.;Ipina, Emiliano Perez;Parlani, Maria;Lee, Se Jong;Yankaskas, Christopher L.;Zhao, Runchen;Mistriotis, Panagiotis;Wang, Nianchao;Gu, Zhizhan;Kalab, Petr;Friedl, Peter;Camley, Brian A.;Konstantopoulos, Konstantinos
细胞调节粘附体连接动力学，以调节多种（病理）生理过程中的上皮完整性，包括癌症转移。我们假设肿瘤周围基质的空间限制性结构通过重塑细胞-细胞粘附相互作用来促进转移细胞的传播。通过将微流体技术与活细胞成像、FLIM/FRET生物传感器和光遗传学工具相结合，研究人员发现，禁闭诱导领导细胞从内聚体中分离。细胞解离是由肌凝蛋白IIA （MIIA）分解e -钙粘蛋白细胞-细胞连接引发的，正如数学模型所概括的那样。升高的MIIA收缩性是由RhoA/ROCK激活控制的，这需要不同的鸟嘌呤核苷酸交换因子（gef）。封闭通过胞质内细胞动力学调节蛋白RacGAP1和Ect2的穿梭激活RhoA，并增加微管动力学，导致活性GEF-H1的释放。因此，限制微环境足以通过微管、核运输和RhoA/ROCK/MIIA通路的相互作用重塑E-cadherin细胞连接，而不是通过下调E-cadherin的表达，诱导细胞从原发肿瘤传播。细胞分裂蛋白通过触发RhoA/myosin IIA拆除e -钙粘蛋白连接来促进领导细胞解离。
Cells tune adherens junction dynamics to regulate epithelial integrity in diverse (patho)physiological processes, including cancer metastasis. We hypothesized that the spatially confining architecture of peritumor stroma promotes metastatic cell dissemination by remodeling cell-cell adhesive interactions. By combining microfluidics with live-cell imaging, FLIM/FRET biosensors, and optogenetic tools, we show that confinement induces leader cell dissociation from cohesive ensembles. Cell dissociation is triggered by myosin IIA (MIIA) dismantling of E-cadherin cell-cell junctions, as recapitulated by a mathematical model. Elevated MIIA contractility is controlled by RhoA/ROCK activation, which requires distinct guanine nucleotide exchange factors (GEFs). Confinement activates RhoA via nucleocytoplasmic shuttling of the cytokinesis-regulatory proteins RacGAP1 and Ect2 and increased microtubule dynamics, which results in the release of active GEF-H1. Thus, confining microenvironments are sufficient to induce cell dissemination from primary tumors by remodeling E-cadherin cell junctions via the interplay of microtubules, nuclear trafficking, and RhoA/ROCK/MIIA pathway and not by down-regulating E-cadherin expression. Cytokinesis proteins promote leader cell dissociation by triggering RhoA/myosin IIA dismantling of E-cadherin junctions.
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影响因子：
21.3
作者：
通讯作者：
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影响因子：
21.3
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
通讯作者：
Friedl P
细胞因子过程中RhoA的时空调节。
DOI：
10.1016/j.cub.2018.03.045
发表时间：
2018-05-07
期刊：
Current biology : CB
影响因子：
--
作者：
Basant A;Glotzer M
通讯作者：
Glotzer M
影响因子：
4.8
作者：
Balzer, Eric M.;Tong, Ziqiu;Konstantopoulos, Konstantinos
通讯作者：
Konstantopoulos, Konstantinos
影响因子：
21.3
作者：
Krendel, M;Zenke, FT;Bokoch, GM
通讯作者：
Bokoch, GM