title: Brain tumour cells interconnect to a functional and resistant network.
abstract: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Osswald
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Jung
authors.affiliation: Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), INF 224, 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Gergely
authors.initials: G
authors.lastname: Solecki
authors.affiliation: Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, 69120 Heidelberg, Germany.
authors.forename: Varun
authors.initials: V
authors.lastname: Venkataramani
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Blaes
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Weil
authors.affiliation: Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, 69120 Heidelberg, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Horstmann
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universität München, 81675 Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Syed
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Lulu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Neurosurgery Clinic, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ratliff
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Kianush
authors.initials: K
authors.lastname: Karimian Jazi
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
authors.forename: Felix T
authors.initials: FT
authors.lastname: Kurz
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schmenger
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lemke
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gömmel
authors.affiliation: Department of Neurophysiology, Institute of Physiology, University of Würzburg, 97070 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Pauli
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Medical Physics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Häring
authors.affiliation: Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), INF 224, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Herl
authors.affiliation: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Steinhäuser
authors.affiliation: Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Damir
authors.initials: D
authors.lastname: Krunic
authors.affiliation: Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Jarahian
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Berghoff
authors.affiliation: Tools For Bio-Imaging, Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Griesbeck
authors.affiliation: Institute of Physiology II, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kalamakis
authors.affiliation: Institute of Physiology II, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Garaschuk
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.|Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4Z6, Canada.|Clark Smith Brain Tumor Research Centre, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany.
authors.forename: Haikun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Heiland
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: CCU Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany.|Department of Radiation Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.affiliation: Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuner
authors.affiliation: Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), INF 224, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D002450:Cell Communication / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D022081:Cell Surface Extensions / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D018031:Connexin 43 / Q000378:metabolism; D018450:Disease Progression; D019922:GAP-43 Protein / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism* / Q000528:radiation effects; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011836:Radiation Tolerance / Q000187:drug effects
chemical_list: D018031:Connexin 43; D019922:GAP-43 Protein