Glioblastomas are incurable tumors infiltrating the brain. A subpopulation of glioblastoma cells forms a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs). Other subpopulations appear unconnected, and their biological role remains unclear. Here, we demonstrate that whole-brain colonization is fueled by glioblastoma cells that lack connections with other tumor cells and astrocytes yet receive synaptic input from neurons. This subpopulation corresponds to neuronal and neural-progenitor-like tumor cell states, as defined by single-cell transcriptomics, both in mouse models and in the human disease. Tumor cell invasion resembled neuronal migration mechanisms and adopted a Lévy-like movement pattern of probing the environment. Neuronal activity induced complex calcium signals in glioblastoma cells followed by the de novo formation of TMs and increased invasion speed. Collectively, superimposing molecular and functional single-cell data revealed that neuronal mechanisms govern glioblastoma cell invasion on multiple levels. This explains how glioblastoma’s dissemination and cellular heterogeneity are closely interlinked.

胶质母细胞瘤是浸润大脑的无法治愈的肿瘤。胶质母细胞瘤细胞亚群形成功能性和抗治疗性肿瘤细胞网络，由肿瘤微管 (TM) 互连。其他亚群似乎没有关联，它们的生物学作用仍不清楚。在这里，我们证明全脑定植是由胶质母细胞瘤细胞推动的，这些细胞缺乏与其他肿瘤细胞和星形胶质细胞的联系，但从神经元接收突触输入。该亚群对应于小鼠模型和人类疾病中的神经元和神经祖细胞样肿瘤细胞状态，如单细胞转录组学所定义。肿瘤细胞侵袭类似于神经元迁移机制，并采用类似 Lévy 的运动模式来探测环境。从头形成 TM 并提高入侵速度。总的来说，叠加分子和功能单细胞数据表明，神经元机制在多个层面上控制胶质母细胞瘤细胞的侵袭。这解释了胶质母细胞瘤的传播和细胞异质性如何密切相关。