Abstract IA011: The Neuroscience of Brain Cancers Michelle Monje, MD PhD Stanford University Howard Hughes Medical Institute

Abstract In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition, while disruption of myelin plasticity contributes to cognitive impairment in a range of disease states. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, the activity of multiple neuron types promotes the growth and invasion of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of tumor-promoting factors and synaptic communication between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses that exhibit synaptic plasticity, and electrically through potassium-evoked currents that are amplified via gap-junctional coupling between tumor cells. This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models and in patients. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer. Citation Format: Michelle Monje. The Neuroscience of Brain Cancers Michelle Monje, MD PhD Stanford University Howard Hughes Medical Institute [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr IA011.