Glioma synapses recruit mechanisms of adaptive plasticity

Kathryn R. Taylor, Tara Barron, Alexa Hui, Avishay Spitzer, Belgin Yalçin, Alexis E. Ivec, Anna C. Geraghty, Griffin G. Hartmann, Marlene Arzt, Shawn M. Gillespie, Yoon Seok Kim, Samin Maleki Jahan, Helena Zhang, Kiarash Shamardani, Minhui Su, Lijun Ni, Peter P. Du, Pamelyn J. Woo, Arianna Silva-Torres, Humsa S. Venkatesh, Rebecca Mancusi, Anitha Ponnuswami, Sara Mulinyawe, Michael B. Keough, Isabelle Chau, Razina Aziz-Bose, Itay Tirosh, Mario L. Suvà and Michelle Monje ()
Additional contact information
Kathryn R. Taylor: Stanford University
Tara Barron: Stanford University
Alexa Hui: Stanford University
Avishay Spitzer: Weizmann Institute of Science
Belgin Yalçin: Stanford University
Alexis E. Ivec: Stanford University
Anna C. Geraghty: Stanford University
Griffin G. Hartmann: Stanford University
Marlene Arzt: Stanford University
Shawn M. Gillespie: Stanford University
Yoon Seok Kim: Stanford University
Samin Maleki Jahan: Stanford University
Helena Zhang: Stanford University
Kiarash Shamardani: Stanford University
Minhui Su: Stanford University
Lijun Ni: Stanford University
Peter P. Du: Stanford University
Pamelyn J. Woo: Stanford University
Arianna Silva-Torres: Stanford University
Humsa S. Venkatesh: Stanford University
Rebecca Mancusi: Stanford University
Anitha Ponnuswami: Stanford University
Sara Mulinyawe: Stanford University
Michael B. Keough: Stanford University
Isabelle Chau: Stanford University
Razina Aziz-Bose: Stanford University
Itay Tirosh: Weizmann Institute of Science
Mario L. Suvà: Massachusetts General Hospital and Harvard Medical School
Michelle Monje: Stanford University

Nature, 2023, vol. 623, issue 7986, 366-374

Abstract: Abstract The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1–3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9–15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17–22 that contributes to memory and learning in the healthy brain23–26. BDNF–TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF–TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

Date: 2023
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DOI: 10.1038/s41586-023-06678-1

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