p120-catenin-dependent collective brain infiltration by glioma cell networks
p120-catenin-dependent collective brain infiltration by glioma cell networks
复制标题
神经胶质瘤细胞网络对p120-连环蛋白依赖的集体脑内浸润的影响
DOI：
10.1038/s41556-019-0443-x
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发表时间：
2020-01-06
影响因子：
21.3
通讯作者：
Friedl, Peter
中科院分区：
文献类型：
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作者：
Gritsenko, Pavlo G.;Atlasy, Nader;Friedl, Peter
Gritsenko等人发现p120-catenin是神经发生和细胞周期通路的调节剂，从而决定胶质瘤细胞之间的细胞间通信并调节集体网络。神经胶质瘤细胞的弥漫性脑浸润导致有害的疾病进展，但其多细胞协调机制尚不清楚。我们在这里展示了神经胶质瘤细胞作为多细胞网络集体浸润大脑。移动的胶质瘤细胞之间的接触是由N-cadherin、β -catenin和p120-catenin稳定的适应性上皮样或丝状连接，它们进行动态周转，传递细胞间钙瞬态并介导定向持久性。p120-catenin的下调会损害细胞间的相互作用和通讯，破坏集体网络，p120-catenin的cadherin和RhoA结合域都是网络形成和迁移所必需的。p120-catenin的失调进一步阻止了小鼠脑弥漫性胶质瘤细胞浸润，导致边缘微病变。转录组学分析已经确定p120-catenin是神经发生和细胞周期途径的上游调节因子，也是胶质瘤患者不良临床结果的预测因子。因此，浸润大脑的集体胶质瘤网络依赖于粘附连接动力学，其靶向可能提供一种意想不到的策略来阻止胶质瘤的进展。
Gritsenko et al. identify p120-catenin as a modulator of neurogenesis and cell cycle pathways, thereby dictating cell-cell communication between glioma cells and regulating collective networks.Diffuse brain infiltration by glioma cells causes detrimental disease progression, but its multicellular coordination is poorly understood. We show here that glioma cells infiltrate the brain collectively as multicellular networks. Contacts between moving glioma cells are adaptive epithelial-like or filamentous junctions stabilized by N-cadherin, beta-catenin and p120-catenin, which undergo kinetic turnover, transmit intercellular calcium transients and mediate directional persistence. Downregulation of p120-catenin compromises cell-cell interaction and communication, disrupts collective networks, and both the cadherin and RhoA binding domains of p120-catenin are required for network formation and migration. Deregulating p120-catenin further prevents diffuse glioma cell infiltration of the mouse brain with marginalized microlesions as the outcome. Transcriptomics analysis has identified p120-catenin as an upstream regulator of neurogenesis and cell cycle pathways and a predictor of poor clinical outcome in glioma patients. Collective glioma networks infiltrating the brain thus depend on adherens junctions dynamics, the targeting of which may offer an unanticipated strategy to halt glioma progression.