Cancer cells can organize and communicate in functional networks. Similarly to other networks in biology and sociology, these can be highly relevant for growth and resilience. In this Perspective, we demonstrate by the example of glioblastomas and other incurable brain tumours how versatile multicellular tumour networks are formed by two classes of long intercellular membrane protrusions: tumour microtubes and tunnelling nanotubes. The resulting networks drive tumour growth and resistance to standard therapies. This raises the question of how to disconnect brain tumour networks to halt tumour growth and whether this can make established therapies more effective. Emerging principles of tumour networks, their potential relevance for tumour types outside the brain and translational implications, including clinical trials that are already based on these discoveries, are discussed.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro Oncol. 22, iv1–iv96 (2020).
Wen, P. Y. et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 22, 1073–1113 (2020).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Bissell, M. J. & Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).
Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).
Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015).
Jung, E. et al. Tweety-homolog 1 drives brain colonization of gliomas. J. Neurosci. 37, 6837–6850 (2017).
Weil, S. et al. Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas. Neuro Oncol. 19, 1316–1326 (2017).
Venkataramani, V. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019).
Xie, R. et al. Tumor cell network integration in glioma represents a stemness feature. Neuro Oncol. 23, 757–769 (2021).
Gritsenko, P. G. et al. p120-catenin-dependent collective brain infiltration by glioma cell networks. Nat. Cell Biol. 22, 97–107 (2020).
Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).
Schneider, M. et al. Meclofenamate causes loss of cellular tethering and decoupling of functional networks in glioblastoma. Neuro Oncol. 23, 1885–1897 (2021).
Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).
Venkatesh, H. S. et al. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature 549, 533–537 (2017).
Portela, M. et al. Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. PLoS Biol. 17, e3000545 (2019).
Pan, Y. et al. NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 594, 277–282 (2021).
Venkataramani, V. & Winkler, F. Activation of retinal neurons triggers tumour formation in cancer-prone mice. Nature 594, 179–180 (2021).
Zuelch, K. J. Brain Tumors: Their Biology and Pathology (English edition based on 2nd German edition; translated by A. B. Rothballer & J. Olszewski). (Springer, 1957).
Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).
Lou, E. et al. Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS ONE 7, e33093 (2012).
Thayanithy, V., Dickson, E. L., Steer, C., Subramanian, S. & Lou, E. Tumor-stromal cross talk: direct cell-to-cell transfer of oncogenic microRNAs via tunneling nanotubes. Transl. Res. 164, 359–365 (2014).
Antanaviciute, I. et al. Long-distance communication between laryngeal carcinoma cells. PLoS ONE 9, e99196 (2014).
Saenz-de-Santa-Maria, I. et al. Control of long-distance cell-to-cell communication and autophagosome transfer in squamous cell carcinoma via tunneling nanotubes. Oncotarget 8, 20939–20960 (2017).
Desir, S. et al. Chemotherapy-induced tunneling nanotubes mediate intercellular drug efflux in pancreatic cancer. Sci. Rep. 8 (2018).
Marlein, C. R. et al. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood 130, 1649–1660 (2017).
Marlein, C. R. et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 79, 2285–2297 (2019).
Linkous, A. et al. Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep. 26, 3203–3211 e5 (2019).
Jung, E. et al. Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma. Nat. Commun. 12, 1014 (2021).
Joseph, J. V. et al. TGF- promotes microtube formation in glioblastoma through thrombospondin 1. Neuro Oncol. https://doi.org/10.1093/neuonc/noab212 (2021).
Skene, J. H. et al. A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes. Science 233, 783–786 (1986).
Aigner, L. & Caroni, P. Absence of persistent spreading, branching, and adhesion in GAP-43-depleted growth cones. J. Cell Biol. 128, 647–660 (1995).
Akers, R. F. & Routtenberg, A. Protein kinase-C phosphorylates a 47-Mr protein (F1) directly related to synaptic plasticity. Brain Res. 334, 147–151 (1985).
Grignaschi, G., Burbassi, S., Zennaro, E., Bendotti, C. & Cervo, L. A single high dose of cocaine induces behavioural sensitization and modifies mRNA encoding GluR1 and GAP-43 in rats. Eur. J. Neurosci. 20, 2833–2837 (2004).
Rekart, J. L., Meiri, K. & Routtenberg, A. Hippocampal-dependent memory is impaired in heterozygous GAP-43 knockout mice. Hippocampus 15, 1–7 (2005).
Suzuki, M. The Drosophila tweety family: molecular candidates for large-conductance Ca2+-activated Cl- channels. Exp. Physiol. 91, 141–147 (2006).
Stefaniuk, M., Swiech, L., Dzwonek, J. & Lukasiuk, K. Expression of Ttyh1, a member of the Tweety family in neurons in vitro and in vivo and its potential role in brain pathology. J. Neurochem. 115, 1183–1194 (2010).
Elia, L. P., Yamamoto, M., Zang, K. & Reichardt, L. F. p120 catenin regulates dendritic spine and synapse development through Rho-family GTPases and cadherins. Neuron 51, 43–56 (2006).
Massague, J. TGF beta signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630 (2012).
Knoferle, J. et al. TGF-beta 1 enhances neurite outgrowth via regulation of proteasome function and EFABP. Neurobiol. Dis. 38, 395–404 (2010).
Tkach, M. & Thery, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226–1232 (2016).
Maas, S. L. N., Breakefield, X. O. & Weaver, A. M. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 27, 172–188 (2017).
Minciacchi, V. R. et al. Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles. Oncotarget 6, 11327–11341 (2015).
Broekman, M. L. et al. Multidimensional communication in the microenvirons of glioblastoma. Nat. Rev. Neurol. 14, 482–495 (2018).
Pinto, G. et al. Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids. Biochemical J. 478, 21–39 (2021).
Pinto, G., Brou, C. & Zurzolo, C. Tunneling nanotubes: the fuel of tumor progression? Trends Cancer 6, 874–888 (2020).
Winkler, F. & Wick, W. Harmful networks in the brain and beyond. Science 359, 1100–1101 (2018).
Ljubojevic, N., Henderson, J. M. & Zurzolo, C. The ways of actin: why tunneling nanotubes are unique cell protrusions. Trends Cell Biol. 31, 130–142 (2021).
Ariazi, J. et al. Tunneling nanotubes and gap junctions-their role in long-range intercellular communication during development, health, and disease conditions. Front. Mol. Neurosci. 10, 333 (2017).
Gerdes, H. H., Rustom, A. & Wang, X. Tunneling nanotubes, an emerging intercellular communication route in development. Mech. Dev. 130, 381–387 (2013).
Inaba, M., Buszczak, M. & Yamashita, Y. M. Nanotubes mediate niche-stem-cell signalling in the Drosophila testis. Nature 523, 329–332 (2015).
Hitomi, M. et al. Differential connexin function enhances self-renewal in glioblastoma. Cell Rep. 11, 1031–1042 (2015).
Wang, J. et al. Targeting different domains of gap junction protein to control malignant glioma. Neuro Oncol. 20, 885–896 (2018).
Hong, X., Sin, W. C., Harris, A. L. & Naus, C. C. Gap junctions modulate glioma invasion by direct transfer of microRNA. Oncotarget 6, 15566–15577 (2015).
Malmersjo, S., Rebellato, P., Smedler, E. & Uhlen, P. Small-world networks of spontaneous Ca2+ activity. Commun. Integr. Biol. 6, e24788 (2013).
Malmersjo, S. et al. Neural progenitors organize in small-world networks to promote cell proliferation. Proc. Natl Acad. Sci. USA 110, E1524–E1532 (2013).
van den Bent, M. J. et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC Brain Tumor Group study 26951. J. Clin. Oncol. 31, 344–350 (2013).
Cairncross, G. et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J. Clin. Oncol. 31, 337–343 (2013).
Scherer, H. J. The forms of growth in gliomas and their practical significance. Brain 63, 1–35 (1940).
Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000).
Ohtaka-Maruyama, C. et al. Synaptic transmission from subplate neurons controls radial migration of neocortical neurons. Science 360, 313–317 (2018).
Zeng, Q. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019).
Kowianski, P. et al. BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell. Mol. Neurobiol. 38, 579–593 (2018).
Aabedi, A. A. et al. Functional alterations in cortical processing of speech in glioma-infiltrated cortex. Proc. Natl Acad. Sci. USA 118 (2021).
Guo, X. et al. Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth. Nat. Commun. 11, 2177 (2020).
Drumm, M. R. et al. Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas. Neuro Oncol. 22, 470–479 (2020).
Sahm, F. et al. Addressing diffuse glioma as a systemic brain disease with single-cell analysis. Arch. Neurol. 69, 523–526 (2012).
Silbergeld, D. L. & Chicoine, M. R. Isolation and characterization of human malignant glioma cells from histologically normal brain. J. Neurosurg. 86, 525–531 (1997).
Giese, A., Bjerkvig, R., Berens, M. E. & Westphal, M. Cost of migration: invasion of malignant gliomas and implications for treatment. J. Clin. Oncol. 21, 1624–1636 (2003).
Darmanis, S. et al. Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep. 21, 1399–1410 (2017).
Garofano, L. et al. Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nat. Cancer 2, 141–156 (2021).
Monje, M. et al. Roadmap for the emerging field of cancer neuroscience. Cell 181, 219–222 (2020).
Weller, M. et al. Glioma. Nat. Rev. Dis. Prim. 1, 15017 (2015).
Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).
Tirosh, I. et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539, 309–313 (2016).
Le, H. T. et al. Gap junction intercellular communication mediated by connexin43 in astrocytes is essential for their resistance to oxidative stress. J. Biol. Chem. 289, 1345–1354 (2014).
Tombal, B., Denmeade, S. R., Gillis, J. M. & Isaacs, J. T. A supramicromolar elevation of intracellular free calcium ([Ca2+]i) is consistently required to induce the execution phase of apoptosis. Cell Death Differ. 9, 561–573 (2002).
Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).
Murphy, S. F. et al. Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. Cancer Res. 76, 139–149 (2016).
Senft, C. et al. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol. 12, 997–1003 (2011).
Stummer, W. et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006).
Konishi, Y., Muragaki, Y., Iseki, H., Mitsuhashi, N. & Okada, Y. Patterns of intracranial glioblastoma recurrence after aggressive surgical resection and adjuvant management: retrospective analysis of 43 cases. Neurol. Med. Chir. 52, 577–586 (2012).
Petrecca, K., Guiot, M. C., Panet-Raymond, V. & Souhami, L. Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma. J. Neurooncol. 111, 19–23 (2013).
Richards, L. M. et al. Gradient of developmental and injury response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity. Nat. Cancer 2, 157–173 (2021).
Horne, E. et al. A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis. Neurooncol. Adv. 3, vdaa165 (2020).
Osswald, M., Solecki, G., Wick, W. & Winkler, F. A malignant cellular network in gliomas: potential clinical implications. Neuro Oncol. 18, 479–485 (2016).
Westhoff, M. A., Zhou, S., Bachem, M. G., Debatin, K. M. & Fulda, S. Identification of a novel switch in the dominant forms of cell adhesion-mediated drug resistance in glioblastoma cells. Oncogene 27, 5169–5181 (2008).
Munoz, J. L. et al. Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis. 5, e1145 (2014).
Potthoff, A. L. et al. Inhibition of gap junctions sensitizes primary glioblastoma cells for temozolomide. Cancers 11, 858 (2019).
Schneider, M. et al. Inhibition of intercellular cytosolic traffic via gap junctions reinforces lomustine-induced toxicity in glioblastoma independent of MGMT promoter methylation status. Pharmaceuticals 14, 195 (2021).
Wallenstein, M. C. & Mauss, E. A. Effect of prostaglandin synthetase inhibitors on experimentally induced convulsions in rats. Pharmacology 29, 85–93 (1984).
Zeyen, T. et al. Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy — the MecMeth/NOA-24 trial. Trials 23, 57 (2022).
Happold, C. et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J. Clin. Oncol. 34, 731–739 (2016).
Krauze, A. V. et al. The addition of valproic acid to concurrent radiation therapy and temozolomide improves patient outcome: a correlative analysis of RTOG 0525, SEER and a phase II NCI trial. Cancer Stud. Ther. https://doi.org/10.31038/cst.2020511 (2020).
Venkataramani, V., Tanev, D. I., Kuner, T., Wick, W. & Winkler, F. Synaptic input to brain tumors: clinical implications. Neuro Oncol. 23, 23–33 (2020).
Vecht, C. et al. Seizure response to perampanel in drug-resistant epilepsy with gliomas: early observations. J. Neurooncol. 133, 603–607 (2017).
Kickingereder, P. et al. Automated quantitative tumour response assessment of MRI in neuro-oncology with artificial neural networks: a multicentre, retrospective study. Lancet Oncol. 20, 728–740 (2019).
Iwamoto, F. M. et al. Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer 116, 1776–1782 (2010).
Grossman, S. A. et al. Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial. J. Clin. Oncol. 27, 4155–4161 (2009).
Rogawski, M. A. & Hanada, T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol. Scand. 127 (Suppl. 197), 19–24 (2013).
Gidal, B. E., Ferry, J., Majid, O. & Hussein, Z. Concentration-effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures. Epilepsia 54, 1490–1497 (2013).
Henley, J. M. & Wilkinson, K. A. Synaptic AMPA receptor composition in development, plasticity and disease. Nat. Rev. Neurosci. 17, 337–350 (2016).
Seol, M. & Kuner, T. Ionotropic glutamate receptor GluA4 and T-type calcium channel Cav 3.1 subunits control key aspects of synaptic transmission at the mouse L5B-POm giant synapse. Eur. J. Neurosci. 42, 3033–3044 (2015).
Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).
Gmiro, V. E., Serdyuk, S. E. & Efremov, O. M. Peripheral and central routes of administration of quaternary ammonium compound IEM-1460 are equally potent in reducing the severity of nicotine-induced seizures in mice. Bull. Exp. Biol. Med. 146, 18–21 (2008).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04295759 (2020).
Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).
Yu, K. et al. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature 578, 166–171 (2020).
Eroglu, C. et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139, 380–392 (2009).
Pine, A. R. et al. Tumor microenvironment is critical for the maintenance of cellular states found in primary glioblastomas. Cancer Discov. 10, 964–979 (2020).
Hara, T. et al. Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma. Cancer Cell 39, 779–792.e11 (2021).
Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).
Network, B. I. C. C. A multimodal cell census and atlas of the mammalian primary motor cortex. Nature 598, 86–102 (2021).
Latario, C. J. et al. Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner. Mol. Biol. Cell 31, 1259–1272 (2020).
Axelrod, R., Axelrod, D. E. & Pienta, K. J. Evolution of cooperation among tumor cells. Proc. Natl Acad. Sci. Usa. 103, 13474–13479 (2006).
Archetti, M. & Pienta, K. J. Cooperation among cancer cells: applying game theory to cancer. Nat. Rev. Cancer 19, 110–117 (2019).
Vishwakarma, M. & Piddini, E. Outcompeting cancer. Nat. Rev. Cancer 20, 187–198 (2020).
Wen, P. Y. et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 28, 1963–1972 (2010).
Schneider, M. et al. Surgery for temporal glioblastoma: lobectomy outranks oncosurgical-based gross-total resection. J. Neurooncol 145, 143–150 (2019).
Pasquier, J. et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J. Transl. Med. 11, 94 (2013).
Burtey, A. et al. Intercellular transfer of transferrin receptor by a contact-, Rab8-dependent mechanism involving tunneling nanotubes. FASEB J. 29, 4695–4712 (2015).
Rimkute, L. et al. The role of neural connexins in HeLa cell mobility and intercellular communication through tunneling tubes. BMC Cell Biol. 17, 3 (2016).
Desir, S. et al. Intercellular transfer of oncogenic KRAS via tunneling nanotubes introduces intracellular mutational heterogeneity in colon cancer cells. Cancers 11, 892 (2019).
Ady, J. W. et al. Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes. Front. Physiol. 5, 400 (2014).
Thayanithy, V. et al. Tumor exosomes induce tunneling nanotubes in lipid raft-enriched regions of human mesothelioma cells. Exp. Cell Res. 323, 178–188 (2014).
Desir, S. et al. Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells. Oncotarget 7, 43150–43161 (2016).
Kretschmer, A. et al. Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer. Sci. Rep. 9, 7826 (2019).
Lu, J. et al. Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells. Oncotarget 8, 15539–15552 (2017).
Polak, R., de Rooij, B., Pieters, R. & den Boer, M. L. B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Blood 126, 2404–2414 (2015).
Wang, J. et al. Cell adhesion-mediated mitochondria transfer contributes to mesenchymal stem cell-induced chemoresistance on T cell acute lymphoblastic leukemia cells. J. Hematol. Oncol. 11, 11 (2018).
Wang, X. & Gerdes, H. H. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ. 22, 1181–1191 (2015).
Bukoreshtliev, N. V. et al. Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett. 583, 1481–1488 (2009).
Wang, X., Bukoreshtliev, N. V. & Gerdes, H. H. Developing neurons form transient nanotubes facilitating electrical coupling and calcium signaling with distant astrocytes. PLoS ONE 7, e47429 (2012).
Berendsen, S. et al. Prognostic relevance of epilepsy at presentation in glioblastoma patients. Neuro Oncol. 18, 700–706 (2016).
van Breemen, M. S., Wilms, E. B. & Vecht, C. J. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 6, 421–430 (2007).
Mastall, M. et al. Survival of brain tumour patients with epilepsy. Brain 44, 3322–3327 (2021).
Buckingham, S. C. et al. Glutamate release by primary brain tumors induces epileptic activity. Nat. Med. 17, 1269–1274 (2011).
de Groot, J. & Sontheimer, H. Glutamate and the biology of gliomas. Glia 59, 1181–1189 (2011).
Hatcher, A. et al. Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model. J. Clin. Invest. 130, 2286–2300 (2020).
Chung, W. J. et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J. Neurosci. 25, 7101–7110 (2005).
Aabedi, A. A. Functional alterations in cortical processing of speech in glioma-infiltrated cortex. Proc. Natl Acad. Sci. USA 118, e2108959118 (2021).
The authors thank Y. Yang and A.-L. Potthoff for figure construction and initial graphical illustrations. F.W. and W.W. were supported by a grant from the German Research Foundation (SFB 1389). V.V. received financial support from the German Research Foundation (VE1373/2-1), Else Kröner-Fresenius-Stiftung (2020-EKEA.135) and the University of Heidelberg (Physician Scientist-Programm and Krebs- und Scharlachstiftung). M.S. was supported by Bonfor and a junior research programme within the Mildred Scheel School of Oncology Cologne-Bonn (project ID 70113307) funded by German Cancer Aid. U.H., M.S. and F.W. received financial support from a grant (01EN2008) from the German Federal Ministry of Education and Research.
F.W. and W.W. are named on patent WO2017020982A1 entitled “Agents for use in the treatment of glioma”. F.W. was a co-founder of DC Europa Ltd (a company trading under the name Divide & Conquer), which is developing new medicines for the treatment of glioma. Divide & Conquer also provides research funding to F.W.’s laboratory under a research collaboration agreement. F.A.G. has received research grants and personal fees from Carl Zeiss Meditec AG, personal fees from Roche Pharma AG and Medac, grants and personal fees from Elekta AB, Bristol-Myers Squibb, MSD Sharp and Dohme GmbH, AstraZeneca and Guerbet SA, stocks, grants and personal fees from Noxxon Pharma AG and non-financial support from Oncare GmbH and Opasca GmbH. U.H. has received speaker honoraria from Medac, Bayer and Novartis and advisory board honoraria from Bayer, Janssen, Noxxon and Karyopharm. All other authors declare no competing interests.
Peer review information
Nature Reviews Cancer thanks David Gutmann, Harald Sontheimer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
(AMPARs). Glutamate receptors and ion (sodium and potassium) channels that are activated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and mediate synaptic transmission at many postsynaptic membranes, where they produce distinct excitatory postsynaptic potentials.
- Contrast-enhancing lesions
Areas on T1-weighted magnetic resonance images that show pathological uptake of a gadolinium-based contrast agent; these may correlate with dense tumour growth and neovascularization.
- Dendritic spine
Postsynaptic membranous protrusion of a neuron’s dendrite that receives synaptic input from another neuron.
- Glutamatergic synaptic contacts
Synapses that have glutamate as their neurotransmitter binding to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors or N-methyl-d-aspartate receptors on the postsynaptic membrane.
- N-Methyl-d-aspartate receptors
Glutamate receptors and ion (including Ca2+) channels that are activated by N-methyl-d-aspartate and that mediate synaptic transmission at many postsynaptic membranes, where they produce distinct excitatory postsynaptic potentials.
- Non-enhancing tumour tissue
Tumour area that is located beyond the contrast-enhancing tumour margin. It is best visualized with clinical imaging on T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging and includes the micro-invading tumour cell front.
Tumour-derived extracellular vesicles that transfer ongogenic messages and protein complexes across cell borders.
- Small-world, scale-free networks
Mathematical network models used to study biological, social and wireless networks.
- Status epilepticus
A condition that results either from the failure of mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures. In clinical use, status epilepticus is operationally defined as a continuous seizure lasting 5 min or longer or two or more seizures between which there is incomplete recovery of consciousness.
- Viral tracing approaches
Methods that use movement of viruses between cells as a label of neuronal projections and potentially trans-synaptic connectivity.
About this article
Cite this article
Venkataramani, V., Schneider, M., Giordano, F.A. et al. Disconnecting multicellular networks in brain tumours. Nat Rev Cancer 22, 481–491 (2022). https://doi.org/10.1038/s41568-022-00475-0
Nature Reviews Cancer (2022)