Autonomous rhythmic activity in glioma networks drives brain tumour growth

David Hausmann, Dirk C. Hoffmann, Varun Venkataramani, Erik Jung, Sandra Horschitz, Svenja K. Tetzlaff, Ammar Jabali, Ling Hai, Tobias Kessler, Daniel D. Azoŕin, Sophie Weil, Alexandros Kourtesakis, Philipp Sievers, Antje Habel, Michael O. Breckwoldt, Matthia A. Karreman, Miriam Ratliff, Julia M. Messmer, Yvonne Yang, Ekin Reyhan, Susann Wendler, Cathrin Löb, Chanté Mayer, Katherine Figarella, Matthias Osswald, Gergely Solecki, Felix Sahm, Olga Garaschuk, Thomas Kuner, Philipp Koch, Matthias Schlesner, Wolfgang Wick and Frank Winkler ()
Additional contact information
David Hausmann: University Hospital Heidelberg
Dirk C. Hoffmann: University Hospital Heidelberg
Varun Venkataramani: University Hospital Heidelberg
Erik Jung: University Hospital Heidelberg
Sandra Horschitz: University of Heidelberg/Medical Faculty Mannheim
Svenja K. Tetzlaff: Heidelberg University
Ammar Jabali: University of Heidelberg/Medical Faculty Mannheim
Ling Hai: University Hospital Heidelberg
Tobias Kessler: University Hospital Heidelberg
Daniel D. Azoŕin: University Hospital Heidelberg
Sophie Weil: University Hospital Heidelberg
Alexandros Kourtesakis: University Hospital Heidelberg
Philipp Sievers: Ruprecht-Karls University Heidelberg
Antje Habel: Ruprecht-Karls University Heidelberg
Michael O. Breckwoldt: Heidelberg University Hospital, University of Heidelberg
Matthia A. Karreman: University Hospital Heidelberg
Miriam Ratliff: German Cancer Research Center (DKFZ)
Julia M. Messmer: German Cancer Research Center (DKFZ)
Yvonne Yang: University Hospital Heidelberg
Ekin Reyhan: University Hospital Heidelberg
Susann Wendler: University Hospital Heidelberg
Cathrin Löb: University Hospital Heidelberg
Chanté Mayer: University Hospital Heidelberg
Katherine Figarella: Eberhard Karls University of Tübingen
Matthias Osswald: University Hospital Heidelberg
Gergely Solecki: University Hospital Heidelberg
Felix Sahm: Ruprecht-Karls University Heidelberg
Olga Garaschuk: Eberhard Karls University of Tübingen
Thomas Kuner: Heidelberg University
Philipp Koch: University of Heidelberg/Medical Faculty Mannheim
Matthias Schlesner: German Cancer Research Center (DKFZ)
Wolfgang Wick: University Hospital Heidelberg
Frank Winkler: University Hospital Heidelberg

Nature, 2023, vol. 613, issue 7942, 179-186

Abstract: Abstract Diffuse gliomas, particularly glioblastomas, are incurable brain tumours1. They are characterized by networks of interconnected brain tumour cells that communicate via Ca2+ transients2–6. However, the networks’ architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and are particularly connected to others. Their autonomous periodic Ca2+ transients preceded Ca2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca2+ activity generates a vulnerability7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs.

Date: 2023
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DOI: 10.1038/s41586-022-05520-4

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