Autonomous rhythmic activity in glioma networks drives brain tumor growth

David Hausmann (1,2), Dirk C. Hoffmann (1,2)+, Varun Venkataramani(1,2,3)+, Erik Jung(1,2)+, Sandra Horschitz(4,5), Svenja K. Tetzlaff(3), Ammar Jabali(4,5), Ling Hai(1,2,6), Tobias Kessler(1,2), Daniel D. Azorín(1,2), Sophie Weil(1,2), Alexandros Kourtesakis(1,2), Philipp Sievers(7,8), Antje Habel(7,8), Michael O. Breckwoldt(9), Matthia A. Karreman(1,2), Miriam Ratliff(2,10), Julia M. Messmer(2,11), Yvonne Yang(1,2), Ekin Reyhan(1,2), Susann Wendler(1,2), Cathrin Löb(1,2), Chanté Mayer(1,2), Katherine Figarella(12), Matthias Osswald(1,2), Gergely Solecki(1,2,13), Felix Sahm(7,8), Olga Garaschuk(12), Thomas Kuner(3), Philipp Koch(4,5), Matthias Schlesner(6,14), Wolfgang Wick(1,2), Frank Winkler(1,2)*

(1) Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. (2) Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. (3) Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany. (4) Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany. (5) Hector Institute for Translational Brain Research (HITBR gGmbH), Mannheim, Germany. (6) Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (7) Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany. (8) Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ),Heidelberg, Germany. (9) Department of Neuroradiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (10) Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany. (11) Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (12) Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany. (13) Business Unit Service and Customer Care, Carl Zeiss Microscopy GmbH, 07745Jena, Germany. (14) Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany. +These authors contributed equally to this work. , *Correspondence to: frank.winkler@med.uni-heidelberg.de

Glioblastoma cell networks harbor a plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and are particularly connected to others. Targeting the autonomous rhythmic activity of periodic tumor cells by pharmacological interference with the potassium channel KCa3.1 strongly compromised global network communication. This led to a marked reduction of tumor cell viability within the entire network, reduced tumor growth in mice, and prolonged animal survival. The dependency of glioblastoma networks on periodic Ca2+ activity generates a vulnerability that can be exploited for the development of novel therapies, with KCa3.1 inhibiting drugs as one example.

To allow reproduction of the performed analysis of microscope images we here provide the codes. Importantly, the Fiji macro needs to be run first and the Matlab codes second.