RT Journal Article
SR Electronic
T1 Glioma synapses recruit mechanisms of adaptive plasticity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.04.467325
DO 10.1101/2021.11.04.467325
A1 Kathryn R. Taylor
A1 Tara Barron
A1 Helena Zhang
A1 Alexa Hui
A1 Griffin Hartmann
A1 Lijun Ni
A1 Humsa S. Venkatesh
A1 Peter Du
A1 Rebecca Mancusi
A1 Belgin Yalçin
A1 Isabelle Chau
A1 Anitha Ponnuswami
A1 Razina Aziz-Bose
A1 Michelle Monje
YR 2021
UL http://biorxiv.org/content/early/2021/11/04/2021.11.04.467325.abstract
AB The nervous system plays an increasingly appreciated role in the regulation of cancer. In malignant gliomas, neuronal activity drives tumor progression not only through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF)1–3, but also through electrophysiologically functional neuron-to-glioma synapses4–6. Malignant synapses are mediated by calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in both pediatric and adult high-grade gliomas4, 5, and consequent depolarization of the glioma cell membrane drives tumor proliferation4. The nervous system exhibits plasticity of both synaptic connectivity and synaptic strength, contributing to neural circuit form and functions. In health, one factor that promotes plasticity of synaptic connectivity7, 8 and strength9–13 is activity-regulated secretion of the neurotrophin BDNF. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF-TrkB (tropomyosin receptor kinase B) signaling. Signaling through the receptor TrkB14, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with the long-term potentiation (LTP)15–23 that is thought to contribute to memory and learning in the healthy brain22,24–27,28, 29. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells exerts growth inhibitory effects in vivo and in neuron:glioma co-cultures that cannot be explained by classical growth factor signaling alone. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.Competing Interest StatementM.M. is on the SAB of Cygnal Therapeutics