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Glutamatergic synaptic input to glioma cells drives brain tumour progression

Author

Listed:
  • Varun Venkataramani

    (Heidelberg University
    University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Dimitar Ivanov Tanev

    (Heidelberg University
    University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Christopher Strahle

    (Heidelberg University)

  • Alexander Studier-Fischer

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Laura Fankhauser

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Tobias Kessler

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Christoph Körber

    (Heidelberg University)

  • Markus Kardorff

    (Heidelberg University)

  • Miriam Ratliff

    (Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    University Hospital Mannheim)

  • Ruifan Xie

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Heinz Horstmann

    (Heidelberg University)

  • Mirko Messer

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Sang Peter Paik

    (Heidelberg University)

  • Johannes Knabbe

    (Heidelberg University)

  • Felix Sahm

    (Ruprecht-Karls University Heidelberg
    Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Felix T. Kurz

    (University Hospital Heidelberg)

  • Azer Aylin Acikgöz

    (Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ))

  • Frank Herrmannsdörfer

    (Heidelberg University)

  • Amit Agarwal

    (Johns Hopkins University School of Medicine
    Heidelberg University)

  • Dwight E. Bergles

    (Heidelberg University)

  • Anthony Chalmers

    (University of Glasgow)

  • Hrvoje Miletic

    (University of Bergen
    Haukeland University Hospital)

  • Sevin Turcan

    (University Hospital Heidelberg)

  • Christian Mawrin

    (Otto-von-Guericke University)

  • Daniel Hänggi

    (University Hospital Mannheim)

  • Hai-Kun Liu

    (Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ))

  • Wolfgang Wick

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Frank Winkler

    (University Hospital Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Thomas Kuner

    (Heidelberg University)

Abstract

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.

Suggested Citation

  • Varun Venkataramani & Dimitar Ivanov Tanev & Christopher Strahle & Alexander Studier-Fischer & Laura Fankhauser & Tobias Kessler & Christoph Körber & Markus Kardorff & Miriam Ratliff & Ruifan Xie & He, 2019. "Glutamatergic synaptic input to glioma cells drives brain tumour progression," Nature, Nature, vol. 573(7775), pages 532-538, September.
    • Handle: RePEc:nat:nature:v:573:y:2019:i:7775:d:10.1038_s41586-019-1564-x
    DOI: 10.1038/s41586-019-1564-x
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    Cited by:

    1. Yanming Ren & Zongyao Huang & Lingling Zhou & Peng Xiao & Junwei Song & Ping He & Chuanxing Xie & Ran Zhou & Menghan Li & Xiangqun Dong & Qing Mao & Chao You & Jianguo Xu & Yanhui Liu & Zhigang Lan & , 2023. "Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Corina Anastasaki & Juan Mo & Ji-Kang Chen & Jit Chatterjee & Yuan Pan & Suzanne M. Scheaffer & Olivia Cobb & Michelle Monje & Lu Q. Le & David H. Gutmann, 2022. "Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. William H. Tomaszewski & Jessica Waibl-Polania & Molly Chakraborty & Jonathan Perera & Jeremy Ratiu & Alexandra Miggelbrink & Donald P. McDonnell & Mustafa Khasraw & David M. Ashley & Peter E. Fecci &, 2022. "Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. 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.
    5. 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.
    6. Dylan Scott Lykke Harwood & Vilde Pedersen & Nicolai Schou Bager & Ane Yde Schmidt & Tobias Overlund Stannius & Aušrinė Areškevičiūtė & Knud Josefsen & Dorte Schou Nørøxe & David Scheie & Hannah Rosta, 2024. "Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Yuanning Zheng & Francisco Carrillo-Perez & Marija Pizurica & Dieter Henrik Heiland & Olivier Gevaert, 2023. "Spatial cellular architecture predicts prognosis in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. 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.
    9. Romain Sigaud & Thomas K. Albert & Caroline Hess & Thomas Hielscher & Nadine Winkler & Daniela Kocher & Carolin Walter & Daniel Münter & Florian Selt & Diren Usta & Jonas Ecker & Angela Brentrup & Mar, 2023. "MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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