Glutamatergic synaptic input to glioma cells drives brain tumour progression

• Published in: Nature (London) Vol. 573; no. 7775; pp. 532 - 538
• Main Authors: Venkataramani, Varun, Tanev, Dimitar Ivanov, Strahle, Christopher, Studier-Fischer, Alexander, Fankhauser, Laura, Kessler, Tobias, Körber, Christoph, Kardorff, Markus, Ratliff, Miriam, Xie, Ruifan, Horstmann, Heinz, Messer, Mirko, Paik, Sang Peter, Knabbe, Johannes, Sahm, Felix, Kurz, Felix T., Acikgöz, Azer Aylin, Herrmannsdörfer, Frank, Agarwal, Amit, Bergles, Dwight E., Chalmers, Anthony, Miletic, Hrvoje, Turcan, Sevin, Mawrin, Christian, Hänggi, Daniel, Liu, Hai-Kun, Wick, Wolfgang, Winkler, Frank, Kuner, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2019; Nature Publishing Group
• Subjects: 14/1; 14/19; 14/28; 14/63; 14/69; 38/91; 631/378/548; 631/67/1059/602; 631/67/1922; 631/67/2321; 631/67/327; 64/60; 82/51; 9/74; Anesthesia; Animals; Autocrine signalling; Brain cancer; Brain Neoplasms - physiopathology; Brain Neoplasms - ultrastructure; Brain tumors; Calcium; Cell adhesion & migration; Cell culture; Cell interactions; Communication; Convulsions & seizures; Disease Models, Animal; Disease Progression; Epilepsy; Gene expression; Glioma; Glioma - physiopathology; Glioma - ultrastructure; Glioma cells; Glutamate receptors; Glutamatergic transmission; Humanities and Social Sciences; Humans; Invasiveness; Mice; Microscopy; Microscopy, Electron, Transmission; multidisciplinary; Neurons; Neurons - physiology; Organic chemistry; Paracrine signalling; Patients; Perturbation; Receptors; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Science; Science (multidisciplinary); Synapses; Synapses - pathology; Tumors; Ultrastructure; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; Germany
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1564-x

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. Neurons form glutamatergic synapses with glioma cells in mice and humans, and inhibition of AMPA receptors reduces glioma cell invasion and growth.