Glutamatergic synaptic input to glioma cells drives brain tumour progression
Open accessAbstract
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.
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Tumor cells in hCOs showed higher proliferation rates than PTs across all three samples.
“Tumor cells in hCOs showed higher prolifera- tion rates than PTs across all three samples (Figures S1G and S1H), consistent with recent findings on glutamate regulation of GBM progression.19,20”
From Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy (2025) · cites this paper as [20]
The tumor microenvironment includes stromal, tumor, endothelial cells, hematopoietic progenitor-derived immune components, and a dense network of adrenergic nerve fibres that influence oncogenesis in brain and non-brain cancers.
“The TME comprises not only stromal, tumor, endothelial cells, and hematopoietic progenitor-derived immune components, but also a dense network of adrenergic nerve fibres that influence oncogenesis in brain and non-brain cancers (94–97).”
From The microbiome and human cancer (2021) · cites this paper as [95]
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- Authors
- Venkataramani, V., Tanev, D. I., Strahle, C., Studier-Fischer, A., Fankhauser, L., Kessler, T., Körber, C., Kardorff, M., Ratliff, M., Xie, R., Horstmann, H., Messer, M., Paik, S. P., Knabbe, J., Sahm, F., Kurz, F. T., Acikgöz, A. A., Herrmannsdörfer, F., Agarwal, A., Bergles, D. E., Chalmers, A., Miletic, H., Turcan, S., Mawrin, C., Hänggi, D., Liu, H.-K., Wick, W., Winkler, F., & Kuner, T.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Johns Hopkins University (US)
- University of Glasgow (GB)
- Otto-von-Guericke-Universität Magdeburg (DE)
- University Medical Centre Mannheim (DE)
- Corresponding author
- Venkataramani, Varun
- Winkler, Frank
- Kuner, Thomas
- ORCID
- Venue
- Nature
- Published
- 2019-09-18
- Volume
- 573
- Issue
- 7775
- Pages
- 532-538
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2973686658
- Cited by
- 1,197
- References
- 37
- Citations by year
- 2026: 207 · 2025: 215 · 2024: 182 · 2023: 178 · 2022: 138 · 2021: 133 · 2020: 127 · 2019: 17
- FWCI
- 58.12
- Type
- journal article
- Language
- en
- Open access
- green
- eprints.gla.ac.uk
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/P001335/1)
- Brain Tumour Charity (26/160)
- Medical Research Council (MR/R009473/1)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- glioma, glutamatergic synapses, AMPA receptors, glutamate receptors, calcium transients, epileptic activity, tumor invasion, tumor growth, perampanel, anesthesia, synaptic ultrastructure, postsynaptic currents
- MeSH terms
- Animals, Brain Neoplasms, Disease Models, Animal, Glioma, Humans, Neurons, Synapses, Receptors, AMPA, Disease Progression, Microscopy, Electron, Transmission, Mice
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