Glioblastoma hijacks neuronal mechanisms for brain invasion
Glioblastoma hijacks neuronal mechanisms for brain invasion
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DOI：
10.1016/j.cell.2022.06.054
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发表时间：
2022-08-05
期刊：
影响因子：
64.5
通讯作者：
Winkler，Frank
中科院分区：
文献类型：
--
作者：
Venkataramani，Varun;Yang，Yvonne;Winkler，Frank
胶质母细胞瘤是一种浸润大脑的无法治愈的肿瘤。胶质母细胞瘤细胞的亚群形成由肿瘤微管（TM）互连的功能性和治疗抗性肿瘤细胞网络。其他亚群似乎没有联系，它们的生物学作用仍然不清楚。在这里，我们证明了全脑定植是由胶质母细胞瘤细胞推动的，这些胶质母细胞瘤细胞缺乏与其他肿瘤细胞和星形胶质细胞的连接，但接受来自神经元的突触输入。该亚群对应于神经元和神经祖细胞样肿瘤细胞状态，如在小鼠模型和人类疾病中通过单细胞转录组学所定义的。肿瘤细胞的侵袭类似于神经元的迁移机制，并采用了Lévy样的运动模式来探测环境。神经元活动诱导胶质母细胞瘤细胞内复杂的钙信号，随后是TM的新生形成和侵袭速度的增加。总的来说，叠加的分子和功能的单细胞数据显示，神经元机制控制胶质母细胞瘤细胞的侵袭在多个层面上。这就解释了胶质母细胞瘤的扩散和细胞异质性是如何密切相关的。
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 thede novoformation 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.