[en] 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.
Disciplines :
Oncology
Author, co-author :
Venkataramani, Varun; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: varun.venkataramani@med.uni-heidelberg.de.
Yang, Yvonne; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Schubert, Marc Cicero; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Reyhan, Ekin; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Tetzlaff, Svenja Kristin; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Wißmann, Niklas; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Botz, Michael; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Soyka, Stella Judith; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Beretta, Carlo Antonio; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Pramatarov, Rangel Lyubomirov; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Fankhauser, Laura; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Garofano, Luciano; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10027, USA.
Freudenberg, Alexander; Institute of Mathematics, University of Mannheim, 68131 Mannheim, Germany.
Wagner, Julia; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Tanev, Dimitar Ivanov; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Ratliff, Miriam; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, Neurosurgery Clinic, University Hospital Mannheim, 68167 Mannheim, Germany.
Xie, Ruifan; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Kessler, Tobias; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Hoffmann, Dirk C; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
Hai, Ling; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Dörflinger, Yvette; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Hoppe, Simone; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
Yabo, Yahaya A; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg.
GOLEBIEWSKA, Anna ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg.
NICLOU, Simone P. ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg.
Sahm, Felix; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Lasorella, Anna; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10027, USA.
Slowik, Martin; Institute of Mathematics, University of Mannheim, 68131 Mannheim, Germany.
Döring, Leif; Institute of Mathematics, University of Mannheim, 68131 Mannheim, Germany.
Iavarone, Antonio; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10027, USA.
Wick, Wolfgang; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Kuner, Thomas; Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: thomas.kuner@uni-heidelberg.de.
Winkler, Frank; Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany, Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: frank.winkler@med.uni-heidelberg.de.
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