Glioma synapses recruit mechanisms of adaptive plasticity: Gene expression in SU-DIPG21 and SU-DIPG25 cell cultures

The nervous system plays an increasingly appreciated role in the regulation of cancer. In gliomas, neuronal activity drives tumor progression through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumor proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signaling through the receptor TrkB (tropomyosin receptor kinase B), 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 synaptic plasticity that contributes to memory and learning in the healthy brain. 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 robustly inhibits tumor progression. 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. Bulk RNA sequencing was performed in patient-derived SU-DIPG21 and SU-DIPG25 cells. RNA was sequenced on the Illumina NextSeq 500 and fpkm values were quantified using featureCounts (Liao et al, 2014). Replicates were performed as indicated in the metadata spreadsheet. Due to patient privacy concerns, we are witholding raw sequencing files at this time. ----------------------------------- Submitters state "Due to patient privacy concerns, we are witholding raw sequencing files at this time."