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Autonomous rhythmic activity in glioma networks drives brain tumour growth

Author

Listed:
  • David Hausmann

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Dirk C. Hoffmann

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Varun Venkataramani

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Erik Jung

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Sandra Horschitz

    (University of Heidelberg/Medical Faculty Mannheim
    Hector Institute for Translational Brain Research (HITBR gGmbH))

  • Svenja K. Tetzlaff

    (Heidelberg University)

  • Ammar Jabali

    (University of Heidelberg/Medical Faculty Mannheim
    Hector Institute for Translational Brain Research (HITBR gGmbH))

  • Ling Hai

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Tobias Kessler

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Daniel D. Azoŕin

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Sophie Weil

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Alexandros Kourtesakis

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Philipp Sievers

    (Ruprecht-Karls University Heidelberg
    German Cancer Research Center (DKFZ))

  • Antje Habel

    (Ruprecht-Karls University Heidelberg
    German Cancer Research Center (DKFZ))

  • Michael O. Breckwoldt

    (Heidelberg University Hospital, University of Heidelberg)

  • Matthia A. Karreman

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Miriam Ratliff

    (German Cancer Research Center (DKFZ)
    University Hospital Mannheim)

  • Julia M. Messmer

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Yvonne Yang

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Ekin Reyhan

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Susann Wendler

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Cathrin Löb

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Chanté Mayer

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Katherine Figarella

    (Eberhard Karls University of Tübingen)

  • Matthias Osswald

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Gergely Solecki

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ)
    Carl Zeiss Microscopy)

  • Felix Sahm

    (Ruprecht-Karls University Heidelberg
    German Cancer Research Center (DKFZ))

  • Olga Garaschuk

    (Eberhard Karls University of Tübingen)

  • Thomas Kuner

    (Heidelberg University)

  • Philipp Koch

    (University of Heidelberg/Medical Faculty Mannheim
    Hector Institute for Translational Brain Research (HITBR gGmbH))

  • Matthias Schlesner

    (German Cancer Research Center (DKFZ)
    Augsburg University)

  • Wolfgang Wick

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

  • Frank Winkler

    (University Hospital Heidelberg
    German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • 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 Kou, 2023. "Autonomous rhythmic activity in glioma networks drives brain tumour growth," Nature, Nature, vol. 613(7942), pages 179-186, January.
  • Handle: RePEc:nat:nature:v:613:y:2023:i:7942:d:10.1038_s41586-022-05520-4
    DOI: 10.1038/s41586-022-05520-4
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    Cited by:

    1. Ling Hai & Dirk C. Hoffmann & Robin J. Wagener & Daniel D. Azorin & David Hausmann & Ruifan Xie & Magnus-Carsten Huppertz & Julien Hiblot & Philipp Sievers & Sophie Heuer & Jakob Ito & Gina Cebulla & , 2024. "A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1," Nature Communications, Nature, vol. 15(1), pages 1-29, December.
    2. Chaitali Chakraborty & Itzel Nissen & Craig A. Vincent & Anna-Carin Hägglund & Andreas Hörnblad & Silvia Remeseiro, 2023. "Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Marc Cicero Schubert & Stella Judith Soyka & Amr Tamimi & Emanuel Maus & Julian Schroers & Niklas Wißmann & Ekin Reyhan & Svenja Kristin Tetzlaff & Yvonne Yang & Robert Denninger & Robin Peretzke & Ca, 2024. "Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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