TY - JOUR
T1 - Glutamatergic synaptic input to glioma cells drives brain tumour progression
AU - Venkataramani, Varun
AU - Tanev, Dimitar Ivanov
AU - Strahle, Christopher
AU - Studier-Fischer, Alexander
AU - Fankhauser, Laura
AU - Kessler, Tobias
AU - Körber, Christoph
AU - Kardorff, Markus
AU - Ratliff, Miriam
AU - Xie, Ruifan
AU - Horstmann, Heinz
AU - Messer, Mirko
AU - Paik, Sang Peter
AU - Knabbe, Johannes
AU - Sahm, Felix
AU - Kurz, Felix T.
AU - Acikgöz, Azer Aylin
AU - Herrmannsdörfer, Frank
AU - Agarwal, Amit
AU - Bergles, Dwight E.
AU - Chalmers, Anthony
AU - Miletic, Hrvoje
AU - Turcan, Sevin
AU - Mawrin, Christian
AU - Hänggi, Daniel
AU - Liu, Hai Kun
AU - Wick, Wolfgang
AU - Winkler, Frank
AU - Kuner, Thomas
N1 - Funding Information:
In summary, blockade of NGS-driven synaptic communication between neurons and GB cells via genetic and pharmacological blockade of AMPAR signalling reduced GB cell malignancy, leading to attenuated glioma progression. This is supported by the functional importance of NGS in incurable paediatric gliomas33.
Funding Information:
Acknowledgements We thank M. Kaiser, S. Hoppe, J. Grosch, S. Weil, I. Sonntag, M. Osswald, K. Gunkel, C. Kocksch, I. Frommer, A. Schlicksupp, R. Rosauer, H.-Y. Nguyen, L. Doerner, M. Schmitt, U. Lindenberger, H. Zheng and S. Wendler for scientific discussion, support and assistance. We thank A. Hotz-Wagenblatt for help with bioinformatic analysis pipelines. We thank M. Suva and I. Tirosh for support with the analysis of single-cell RNA-seq databases from human gliomas, C. Steinhäuser and R. Jabs for advice on how to perform electrophysiological recordings from non-neuronal postsynaptic cells and the EM Core Facility of University Heidelberg for general support. We thank M. Monje for stably transducing our S24 glioma cell line with ChR2(H134R). We thank C. Watts for generating and providing the E2 primary glioblastoma cell line. A.A. was supported by the Chica and Heinz Schaller research foundation and the grant from the Deutsche Forschungsgemeinschaft (AG 287/1-1). V.V. was supported by the MD/PhD program of the Medical Faculty Heidelberg and the Stiftung für Krebs-und Scharlachforschung. D.I.T. was supported by the Deutsche Krebshilfe. W.W. and F.W. were supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 1389). F.W. was supported by a grant from the Deutsche Forschungsgemeinschaft (WI 1930/6). T. Kuner was supported by the CellNetworks Excellence Cluster (EXC 81). F.W. and T. Kuner acknowledge their children Jakob and Manili, respectively, for seeding this collaboration.
PY - 2019/9/26
Y1 - 2019/9/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072687457&partnerID=8YFLogxK
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U2 - 10.1038/s41586-019-1564-x
DO - 10.1038/s41586-019-1564-x
M3 - Article
C2 - 31534219
AN - SCOPUS:85072687457
VL - 573
SP - 532
EP - 538
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7775
ER -