Glioblastoma hijacks neuronal mechanisms for brain invasion

Venkataramani, Varun ; Yang, Yvonne ; Schubert, Marc Cicero ; Reyhan, Ekin ; Tetzlaff, Svenja Kristin ; Wißmann, Niklas ; Botz, Michael ; Soyka, Stella Judith ; Beretta, Carlo Antonio ; Pramatarov, Rangel Lyubomirov ; Fankhauser, Laura ; Garofano, Luciano ; Freudenberg, Alexander ; Wagner, Julia ; Tanev, Dimitar Ivanov ; Ratliff, Miriam ; Xie, Ruifan ; Kessler, Tobias ; Hoffmann, Dirk C. ; Hai, Ling ; Dörflinger, Yvette ; Hoppe, Simone ; Yabo, Yahaya A. ; Golebiewska, Anna ; Niclou, Simone P. ; Sahm, Felix ; Lasorella, Anna ; Slowik, Martin ; Döring, Leif ; Iavarone, Antonio ; Wick, Wolfgang ; Kuner, Thomas ; Winkler, Frank

DOI:	https://doi.org/10.1016/j.cell.2022.06.054
URL:	https://www.sciencedirect.com/science/article/abs/...
Additional URL:	https://www.cell.com/cell/pdf/S0092-8674(22)00847-...
Document Type:	Article
Year of publication:	2022
The title of a journal, publication series:	Cell
Volume:	185
Issue number:	16, e31
Page range:	2899-2917
Place of publication:	Cambridge, Mass.
Publishing house:	Cell Press
ISSN:	0092-8674 , 1097-4172
Publication language:	English
Institution:	School of Business Informatics and Mathematics > Stochastics (Junioprofessur) (Slowik 2021-)
Subject:	610 Medicine and health
Abstract:	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.