Glutamatergic synaptic input to glioma cells drives brain tumour progression.
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
28
09
2018
accepted:
09
08
2019
pubmed:
20
9
2019
medline:
28
3
2020
entrez:
20
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31534219
doi: 10.1038/s41586-019-1564-x
pii: 10.1038/s41586-019-1564-x
doi:
Substances chimiques
Receptors, AMPA
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
532-538Subventions
Organisme : Medical Research Council
ID : G0802755
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R009473/1
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/P001335/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Références
Scherer, H. J. A critical review: the pathology of cerebral gliomas. J. Neurol. Psychiatry 3, 147–177 (1940).
doi: 10.1136/jnnp.3.2.147
Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).
doi: 10.1016/j.cell.2015.04.012
Venkatesh, H. S. et al. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature 549, 533–537 (2017).
doi: 10.1038/nature24014
Ishiuchi, S. et al. Blockage of Ca
doi: 10.1038/nm746
Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nat. Med. 7, 1010–1015 (2001).
doi: 10.1038/nm0901-1010
Savaskan, N. E. et al. Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema. Nat. Med. 14, 629–632 (2008).
doi: 10.1038/nm1772
Rzeski, W., Turski, L. & Ikonomidou, C. Glutamate antagonists limit tumor growth. Proc. Natl Acad. Sci. USA 98, 6372–6377 (2001).
doi: 10.1073/pnas.091113598
Li, L. & Hanahan, D. Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell 153, 86–100 (2013).
doi: 10.1016/j.cell.2013.02.051
Li, L. et al. GKAP acts as a genetic modulator of NMDAR signaling to govern invasive tumor growth. Cancer Cell 33, 736–751 (2018).
doi: 10.1016/j.ccell.2018.02.011
Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015).
doi: 10.1038/nature16071
Jung, E. et al. Tweety-homolog 1 drives brain colonization of gliomas. J. Neurosci. 37, 6837–6850 (2017).
doi: 10.1523/JNEUROSCI.3532-16.2017
Weil, S. et al. Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas. Neuro-oncol. 19, 1316–1326 (2017).
doi: 10.1093/neuonc/nox070
Zhu, Z. et al. Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival. Cell Stem Cell 15, 185–198 (2014).
doi: 10.1016/j.stem.2014.04.007
Harris, K. M. & Weinberg, R. J. Ultrastructure of synapses in the mammalian brain. Cold Spring Harb. Perspect. Biol. 4, a005587 (2012).
doi: 10.1101/cshperspect.a005587
Gray, E. G. Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron microscope study. J. Anat. 93, 420–433 (1959).
pubmed: 13829103
pmcid: 1244535
Venteicher, A. S. et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 355, eaai8478 (2017).
doi: 10.1126/science.aai8478
Darmanis, S. et al. Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Reports 21, 1399–1410 (2017).
doi: 10.1016/j.celrep.2017.10.030
Maas, S., Patt, S., Schrey, M. & Rich, A. Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc. Natl Acad. Sci. USA 98, 14687–14692 (2001).
doi: 10.1073/pnas.251531398
Sommer, B., Köhler, M., Sprengel, R. & Seeburg, P. H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11–19 (1991).
doi: 10.1016/0092-8674(91)90568-J
Burnashev, N., Monyer, H., Seeburg, P. H. & Sakmann, B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8, 189–198 (1992).
doi: 10.1016/0896-6273(92)90120-3
Dalva, M. B., McClelland, A. C. & Kayser, M. S. Cell adhesion molecules: signalling functions at the synapse. Nat. Rev. Neurosci. 8, 206–220 (2007).
doi: 10.1038/nrn2075
John Lin, C. C. et al. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20, 396–405 (2017).
doi: 10.1038/nn.4493
Mosbacher, J. et al. A molecular determinant for submillisecond desensitization in glutamate receptors. Science 266, 1059–1062 (1994).
doi: 10.1126/science.7973663
Traynelis, S. F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).
doi: 10.1124/pr.109.002451
Bergles, D. E., Diamond, J. S. & Jahr, C. E. Clearance of glutamate inside the synapse and beyond. Curr. Opin. Neurobiol. 9, 293–298 (1999).
doi: 10.1016/S0959-4388(99)80043-9
Korber, V. et al. Evolutionary trajectories of IDH
doi: 10.1016/j.ccell.2019.02.007
Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).
doi: 10.1126/science.1254257
Chaichana, K. L., Parker, S. L., Olivi, A. & Quiñones-Hinojosa, A. Long-term seizure outcomes in adult patients undergoing primary resection of malignant brain astrocytomas. J. Neurosurg. 111, 282–292 (2009).
doi: 10.3171/2009.2.JNS081132
Weller, M., Stupp, R. & Wick, W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol. 13, e375–e382 (2012).
doi: 10.1016/S1470-2045(12)70266-8
Ohtaka-Maruyama, C. et al. Synaptic transmission from subplate neurons controls radial migration of neocortical neurons. Science 360, 313–317 (2018).
doi: 10.1126/science.aar2866
de Groot, J. & Sontheimer, H. Glutamate and the biology of gliomas. Glia 59, 1181–1189 (2011).
doi: 10.1002/glia.21113
Izumoto, S. et al. Seizures and tumor progression in glioma patients with uncontrollable epilepsy treated with perampanel. Anticancer Res. 38, 4361–4366 (2018).
doi: 10.21873/anticanres.12737
Venkatesh, H. et al. Electrical and synaptic integration of glioma into neural circuits. Nature https://doi.org/10.1038/s41586-019-1563-y (2019).
Gibson, E. M. et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344, 1252304 (2014).
doi: 10.1126/science.1252304
Buckingham, S. C. et al. Glutamate release by primary brain tumors induces epileptic activity. Nat. Med. 17, 1269–1274 (2011).
doi: 10.1038/nm.2453
Huberfeld, G. & Vecht, C. J. Seizures and gliomas-towards a single therapeutic approach. Nat. Rev. Neurol. 12, 204–216 (2016).
doi: 10.1038/nrneurol.2016.26
Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).
doi: 10.1016/j.ccr.2009.12.020