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Disconnecting multicellular networks in brain tumours

Nature Reviews Cancer volume 22, pages 481–491 (2022)Cite this article

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Abstract

Cancer cells can organize and communicate in functional networks. Similarly to other networks in biology and sociology, these can be highly relevant for growth and resilience. In this Perspective, we demonstrate by the example of glioblastomas and other incurable brain tumours how versatile multicellular tumour networks are formed by two classes of long intercellular membrane protrusions: tumour microtubes and tunnelling nanotubes. The resulting networks drive tumour growth and resistance to standard therapies. This raises the question of how to disconnect brain tumour networks to halt tumour growth and whether this can make established therapies more effective. Emerging principles of tumour networks, their potential relevance for tumour types outside the brain and translational implications, including clinical trials that are already based on these discoveries, are discussed.

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Fig. 1: Heterogeneous and cooperative tumour networks in glioma.
Fig. 2: Potential strategies for therapeutic disconnection.

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Acknowledgements

The authors thank Y. Yang and A.-L. Potthoff for figure construction and initial graphical illustrations. F.W. and W.W. were supported by a grant from the German Research Foundation (SFB 1389). V.V. received financial support from the German Research Foundation (VE1373/2-1), Else Kröner-Fresenius-Stiftung (2020-EKEA.135) and the University of Heidelberg (Physician Scientist-Programm and Krebs- und Scharlachstiftung). M.S. was supported by Bonfor and a junior research programme within the Mildred Scheel School of Oncology Cologne-Bonn (project ID 70113307) funded by German Cancer Aid. U.H., M.S. and F.W. received financial support from a grant (01EN2008) from the German Federal Ministry of Education and Research.

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Author notes

  1. These authors contributed equally: Varun Venkataramani, Matthias Schneider, Ulrich Herrlinger, Frank Winkler.

Authors and Affiliations

  1. Neurology Clinic, University Hospital Heidelberg, Heidelberg, Germany

    Varun Venkataramani, Wolfgang Wick & Frank Winkler

  2. National Center for Tumour Diseases, University Hospital Heidelberg, Heidelberg, Germany

    Varun Venkataramani, Wolfgang Wick & Frank Winkler

  3. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Varun Venkataramani, Wolfgang Wick & Frank Winkler

  4. Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany

    Varun Venkataramani & Thomas Kuner

  5. Department of Neurosurgery, University Hospital Bonn, Bonn, Germany

    Matthias Schneider

  6. Department of Radiation Oncology, University Hospital Bonn, University of Bonn, Bonn, Germany

    Frank Anton Giordano

  7. Division of Clinical Neurooncology, Department of Neurology, University Hospital Bonn, University of Bonn, Bonn, Germany

    Ulrich Herrlinger

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  1. Varun Venkataramani
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Contributions

V.V., M.S., U.H. and F.W. researched data for the article. V.V., M.S., T.K., U.H. and F.W. contributed substantially to discussion of the content. V.V., M.S., F.A.G., W.W., U.H. and F.W. wrote the article. V.V., M.S., F.A.G., T.K., W.W., U.H. and F.W. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Varun Venkataramani, Matthias Schneider, Ulrich Herrlinger or Frank Winkler.

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Competing interests

F.W. and W.W. are named on patent WO2017020982A1 entitled “Agents for use in the treatment of glioma”. F.W. was a co-founder of DC Europa Ltd (a company trading under the name Divide & Conquer), which is developing new medicines for the treatment of glioma. Divide & Conquer also provides research funding to F.W.’s laboratory under a research collaboration agreement. F.A.G. has received research grants and personal fees from Carl Zeiss Meditec AG, personal fees from Roche Pharma AG and Medac, grants and personal fees from Elekta AB, Bristol-Myers Squibb, MSD Sharp and Dohme GmbH, AstraZeneca and Guerbet SA, stocks, grants and personal fees from Noxxon Pharma AG and non-financial support from Oncare GmbH and Opasca GmbH. U.H. has received speaker honoraria from Medac, Bayer and Novartis and advisory board honoraria from Bayer, Janssen, Noxxon and Karyopharm. All other authors declare no competing interests.

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Nature Reviews Cancer thanks David Gutmann, Harald Sontheimer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors

(AMPARs). Glutamate receptors and ion (sodium and potassium) channels that are activated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and mediate synaptic transmission at many postsynaptic membranes, where they produce distinct excitatory postsynaptic potentials.

Contrast-enhancing lesions

Areas on T1-weighted magnetic resonance images that show pathological uptake of a gadolinium-based contrast agent; these may correlate with dense tumour growth and neovascularization.

Dendritic spine

Postsynaptic membranous protrusion of a neuron’s dendrite that receives synaptic input from another neuron.

Glutamatergic synaptic contacts

Synapses that have glutamate as their neurotransmitter binding to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors or N-methyl-d-aspartate receptors on the postsynaptic membrane.

N-Methyl-d-aspartate receptors

Glutamate receptors and ion (including Ca2+) channels that are activated by N-methyl-d-aspartate and that mediate synaptic transmission at many postsynaptic membranes, where they produce distinct excitatory postsynaptic potentials.

Non-enhancing tumour tissue

Tumour area that is located beyond the contrast-enhancing tumour margin. It is best visualized with clinical imaging on T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging and includes the micro-invading tumour cell front.

Oncosomes

Tumour-derived extracellular vesicles that transfer ongogenic messages and protein complexes across cell borders.

Small-world, scale-free networks

Mathematical network models used to study biological, social and wireless networks.

Status epilepticus

A condition that results either from the failure of mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures. In clinical use, status epilepticus is operationally defined as a continuous seizure lasting 5 min or longer or two or more seizures between which there is incomplete recovery of consciousness.

Viral tracing approaches

Methods that use movement of viruses between cells as a label of neuronal projections and potentially trans-synaptic connectivity.

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Venkataramani, V., Schneider, M., Giordano, F.A. et al. Disconnecting multicellular networks in brain tumours. Nat Rev Cancer 22, 481–491 (2022). https://doi.org/10.1038/s41568-022-00475-0

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