Brain tumour cells interconnect to a functional and resistant network

Matthias Osswald, Erik Jung, Felix Sahm, Gergely Solecki, Varun Venkataramani, Jonas Blaes, Sophie Weil, Heinz Horstmann, Benedikt Wiestler, Mustafa Syed, Lulu Huang, Miriam Ratliff, Kianush Karimian Jazi, Felix T. Kurz, Torsten Schmenger, Dieter Lemke, Miriam Gömmel, Martin Pauli, Yunxiang Liao, Peter Häring, Stefan Pusch, Verena Herl, Christian Steinhäuser, Damir Krunic, Mostafa Jarahian, Hrvoje Miletic, Anna S. Berghoff, Oliver Griesbeck, Georgios Kalamakis, Olga Garaschuk, Matthias Preusser, Samuel Weiss, Haikun Liu, Sabine Heiland, Michael Platten, Peter E. Huber, Thomas Kuner, Andreas von Deimling, Wolfgang Wick and Frank Winkler ()
Additional contact information
Matthias Osswald: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Erik Jung: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Felix Sahm: Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224
Gergely Solecki: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Varun Venkataramani: Institute of Anatomy and Cell Biology, Heidelberg University, INF 307
Jonas Blaes: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Sophie Weil: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Heinz Horstmann: Institute of Anatomy and Cell Biology, Heidelberg University, INF 307
Benedikt Wiestler: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Mustafa Syed: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Lulu Huang: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Miriam Ratliff: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Kianush Karimian Jazi: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Felix T. Kurz: University Hospital Heidelberg, INF 400
Torsten Schmenger: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Dieter Lemke: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Miriam Gömmel: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Martin Pauli: Institute of Physiology, University of Würzburg
Yunxiang Liao: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Peter Häring: German Cancer Research Center (DKFZ)
Stefan Pusch: Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224
Verena Herl: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25
Christian Steinhäuser: Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25
Damir Krunic: Light Microscopy Facility, German Cancer Research Center (DKFZ)
Mostafa Jarahian: German Cancer Research Center (DKFZ)
Hrvoje Miletic: University of Bergen, Jonas Lies vei 91
Anna S. Berghoff: Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna
Oliver Griesbeck: Tools For Bio-Imaging, Max-Planck-Institute of Neurobiology
Georgios Kalamakis: Institute of Physiology II, Eberhard Karls University of Tübingen
Olga Garaschuk: Institute of Physiology II, Eberhard Karls University of Tübingen
Matthias Preusser: Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna
Samuel Weiss: Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary
Haikun Liu: Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), INF 280
Sabine Heiland: University Hospital Heidelberg, INF 400
Michael Platten: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Peter E. Huber: CCU Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), INF 280
Thomas Kuner: Institute of Anatomy and Cell Biology, Heidelberg University, INF 307
Andreas von Deimling: Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224
Wolfgang Wick: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400
Frank Winkler: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400

Nature, 2015, vol. 528, issue 7580, 93-98

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature16071

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