Neuron-glial Interactions in Health and Disease: From Cognition to Cancer

Event Details

Type

Friday Lecture Series

Speaker(s)

Michelle Monje, M.D., Ph.D., professor of neurology and neurological sciences, Stanford School of Medicine; investigator, Howard Hughes Medical Institute

Speaker bio(s)

FLS lectures will take place in Caspary Auditorium and virtually via Zoom. We recommend virtual participants log out of VPN prior to logging in to Zoom. Please do not share the link or post on social media.

Michelle Monje, MD, PhD, is a Professor of Neurology at Stanford University and a Howard Hughes Medical Institute Investigator. She received her M.D. and Ph.D. in Neuroscience from Stanford and completed her residency training in neurology at the Massachusetts General Hospital/Brigham and Women's Hospital/Harvard Medical School Partners program, and then returned to Stanford for a clinical fellowship in pediatric neuro-oncology. Her research program focuses at the intersection of neuroscience, immunology and brain cancer biology with an emphasis on neuron-glial interactions in health and oncological disease. Her laboratory studies how neuronal activity regulates healthy glial precursor cell proliferation, new oligodendrocyte generation, and adaptive myelination; this plasticity of myelin contributes to healthy cognitive function, while disruption of myelin plasticity contributes to cognitive impairment in disease states like cancer therapy-related cognitive impairment. Her lab discovered that neuronal activity similarly promotes the progression of malignant gliomas, driving glioma growth through both paracrine factors and through electrophysiologically functional neuron-to-glioma synapses. Dr.Monje has led several of her discoveries from basic molecular work to clinical trials. Her work has been recognized with numerous honors, including an NIH Director’s Pioneer Award, a MacArthur Fellowship, the Richard Lounsbery Award from the National Academy of Sciences and election to the National Academy of Medicine.­­

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 cancer therapy-related cognitive impairment. 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, neuronal activity promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses, and electrically through potassium-evoked currents that are amplified through gap-junctional coupling between tumor cells This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic 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.

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Tri-Institutional