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, β-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.

神经胶质瘤细胞的弥漫性脑浸润会导致有害的疾病进展，但其多细胞协调机制尚不清楚。我们在这里表明，神经胶质瘤细胞作为多细胞网络共同浸润大脑。移动的神经胶质瘤细胞之间的接触是由 N-钙粘蛋白、β-连环蛋白和 p120-连环蛋白稳定的适应性上皮样或丝状连接，它们经历动力转换、传递细胞间钙瞬变并介导定向持久性。p120-连环蛋白的下调会损害细胞间的相互作用和通讯，破坏集体网络，并且 p120-连环蛋白的钙粘蛋白和 RhoA 结合域都是网络形成和迁移所必需的。解除 p120-连环蛋白的调节可进一步防止弥漫性神经胶质瘤细胞浸润小鼠大脑，从而导致边缘化微病变。转录组学分析已确定 p120-catenin 是神经发生和细胞周期途径的上游调节因子，也是神经胶质瘤患者不良临床结果的预测因子。因此，浸润大脑的集体神经胶质瘤网络依赖于粘附连接的动态，其靶向可能提供一种意想不到的策略来阻止神经胶质瘤的进展。