TY - JOUR
T1 - Glioblastoma hijacks neuronal mechanisms for brain invasion
AU - Venkataramani, Varun
AU - Yang, Yvonne
AU - Schubert, Marc Cicero
AU - Reyhan, Ekin
AU - Tetzlaff, Svenja Kristin
AU - Wißmann, Niklas
AU - Botz, Michael
AU - Soyka, Stella Judith
AU - Beretta, Carlo Antonio
AU - Pramatarov, Rangel Lyubomirov
AU - Fankhauser, Laura
AU - Garofano, Luciano
AU - Freudenberg, Alexander
AU - Wagner, Julia
AU - Tanev, Dimitar Ivanov
AU - Ratliff, Miriam
AU - Xie, Ruifan
AU - Kessler, Tobias
AU - Hoffmann, Dirk C.
AU - Hai, Ling
AU - Dörflinger, Yvette
AU - Hoppe, Simone
AU - Yabo, Yahaya A.
AU - Golebiewska, Anna
AU - Niclou, Simone P.
AU - Sahm, Felix
AU - Lasorella, Anna
AU - Slowik, Martin
AU - Döring, Leif
AU - Iavarone, Antonio
AU - Wick, Wolfgang
AU - Kuner, Thomas
AU - Winkler, Frank
N1 - ACKNOWLEDGMENTS
V.V. received financial support from the German Research Foundation (DFG: VE1373/2-1), the Else Kro¨ ner-Fresenius-Stiftung (2020-EKEA.135) and the Medical Faculty of Heidelberg University (Physician-Scientist-Program, Krebs-und Scharlachstiftung). Y.Y., M.C.S., S.K.T., E.R., and D.I.T. were supported by the Deutsche Krebshilfe/German Cancer Aid (Mildred-Scheel- Scholarship forMDstudents). V.V., T. Kessler, W.W., and F.W. were supported by a grant from the German Research Foundation (DFG: SFB 1389). Y.A.Y., A.G., and S.P.N. were supported by GLIOTRAIN ITN H2020 grant no. 766069. We gratefully acknowledge the data storage service SDS@hd supported by the Ministry of Science, Research, and the Arts Baden-Wu¨ rttemberg (MWK).
Copyright © 2022 Elsevier Inc. All rights reserved.
PY - 2022/8/4
Y1 - 2022/8/4
N2 - 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.
AB - 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.
KW - cancer neuroscience
KW - cell heterogeneity
KW - glioblastoma
KW - glutamatergic synapse
KW - neurogliomal synapses
KW - neuron-tumor interaction
KW - tumor cell networks
KW - tumor microtubes
UR - http://www.scopus.com/inward/record.url?scp=85135599975&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35914528
U2 - 10.1016/j.cell.2022.06.054
DO - 10.1016/j.cell.2022.06.054
M3 - Article
C2 - 35914528
SN - 0092-8674
VL - 185
SP - 2899-2917.e31
JO - Cell
JF - Cell
IS - 16
ER -