CNSC-17. Glioma Synapses Recruit Mechanisms of Adaptive Plasticity

Abstract

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), but also through electrophysiologically functional neuron-to-glioma synapses. 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 gliomas, and consequent depolarization of the glioma cell membrane drives tumor proliferation. 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 connectivity and strength 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 TrkB, 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) that is thought to contribute 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 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. While targeting Trk signaling is presently being explored for NTRK-fusion brain tumors, these findings indicate that BDNF-TrkB signaling may also represent an important therapeutic target for NTRK2 wildtype gliomas.

Spatial Transcriptomic Sequencing of a DIPG-infiltrated Brainstem reveals Key Invasion Markers and Novel Ligand-Receptor Pairs contributing to Tumour to TME Crosstalk

“…This peptide has been previously demonstrated to be a critical regulator for BDNF-TrkB signalling [37, 38]. The importance of this pathway contributing to neuron-to-glioma synapse formation and plasticity was highlighted only recently by Taylor and colleagues [39]. We also observed TIMP1 (Tissue inhibitor matrix metalloproteinase 1) highly expressed and positively correlated with distal regions.…”

“…Ca 2+ -dependent PLC and PKC signalling is widely implicated in synaptic plasticity and the importance of Ca 2+ signalling to modulate synaptic strength in DIPG is well established [39,55,56]. Most intriguingly, the PACAP-mediated pathway has been implicated to play a notable role in chronic migraine and a phase II clinical trial (NCT04976309) targeting this neuropeptide is currently under investigation [57][58][59].…”

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition

“…For example, our results suggest that AZD8055 will both reduce hyperexcitability and render excitatory neurons more sensitive to drugs that modulate inhibitory tone, such as traditional GABAergic anticonvulsants. These combined effects could improve glioma-associated seizure treatment, and other neurological dysfunctions, while also potentially reducing the growth-promoting effects that neuronal activity appears to have on glioma cells 21,[23][24][25][26][27][28][29][30][31][32][33] . Furthermore, the loss of dendritic spines and postsynaptic structures that is seen at the margin of glioma may provide fertile ground for infiltrating glioma cells to successfully compete for synaptic input.…”

“…Notably, seizures and functional reorganization primarily occurs at the infiltrative margin of glioma 10,[19][20][21] , and it has been proposed that glioma-associated neuroplasticity may contribute to the development of these seizures 1,12,22 . There is also evidence from experimental models that glioma growth and proliferation are affected by neuronal activity 21,[23][24][25][26][27][28][29][30][31][32][33] , further highlighting the clinical importance of developing effective ways to normalize neuronal function as a means to treat neurological symptoms and slow tumor growth. However, glioma-induced neuronal alterations have yet to be adequately characterized on a cellular-level either by in vivo imaging, molecular profiling, or structural morphology.…”

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions

“…Progress within this field may therefore represent an important new research avenue related to GBM therapy. Yet, despite these significant advances [8,9], it remains unclear how tumor cellular/host interactions regulate tumor cell proliferation and invasion, ultimately determining patient outcome.…”