| First Author | Taylor KR | Year | 2023 |
| Journal | Nature | Volume | 623 |
| Issue | 7986 | Pages | 366-374 |
| PubMed ID | 37914930 | Mgi Jnum | J:371222 |
| Mgi Id | MGI:7647091 | Doi | 10.1038/s41586-023-06678-1 |
| Citation | Taylor KR, et al. (2023) Glioma synapses recruit mechanisms of adaptive plasticity. Nature 623(7986):366-374 |
| abstractText | 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 factor(1-3) (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors(4,5). The consequent glioma cell membrane depolarization drives tumour proliferation(4,6). In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity(7,8) and strength(9-15). Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B(16) (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 plasticity(17-22) that contributes to memory and learning in the healthy brain(23-26). 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. |
