IMPACT OF NEUROTRANSMITTER RELEASE ON HIGH-GRADE GLIOMA SIGNALING DYNAMICS

Diffuse midline glioma (DMG) is a subclass of high-grade brain tumors, responsible for low survival rates in pediatric patients due, in part, to the particularly infiltrative nature of its glia-like cells into neuronal networks. Originating in deep brain regions, such as the thalamus and brainstem, DMGs have complex, heterogenous tumor architectures, which present diverse, spatially distinct features. Due to the scarcity of surgical biopsied specimen, there is a need for alternative approaches to understand the mechanisms of tumor interactions with its microenvironment. In vivo studies have shown that neurogliomal synapses form during tumor invasion, whereby glioma cells hijack innate neural circuitry and utilize secreted factors to enhance their proliferative capabilities and therapeutic resistance. Intracellular calcium signaling mediates tumorigenic activity and has been shown to be increased in glioma cells in response to activity-mediated release of neurotransmitters such as glutamate, GABA, and acetylcholine. The influence of other neuronal subtypes, including dopaminergic and serotoninergic neurons, on glioma signaling is currently understudied, despite their presence at DMG’s tumoral point of origin. To dissect the role of various neuronal signaling cues on glioma calcium dynamics and invasion phenotypes, we performed an in vitro neurotransmitter screen on DMG monocultures. Our results show that chemical messengers differentially shape calcium dynamics and downstream molecular programs in tumor cells. With this, we aim to identify postsynaptic receptors whose selective pharmacological targeting most effectively disrupt neuron–tumor connectivity.