I am a neuroscientist and pediatric neuro-oncologist whose research program focuses at the intersection of neuroscience, immunology and brain cancer biology in childhood gliomas. Intercellular interactions between neurons, neural precursor cells, microglia, oligodendroglia and astrocytes that regulate normal glial function (Science 2014) and malignant glioma (Cell 2015; Nature 2019) have been one major area of focus. Microglial interactions with neurons and neural precursor cells and microglial-mediated disruption of neuroplasticity mechanisms underlying cognitive dysfunction following cancer therapies is another long-standing area of deep focus (Cell 2019). Together with these basic studies, my research program innovated the development of patient-derived models of diffuse intrinsic pontine glioma (DIPG) and other pediatric gliomas and using these new resources have executed preclinical studies of novel therapeutics for DIPG, H3K27M+ diffuse midline gliomas and other forms of childhood gliomas in order to translate new therapies to the clinic. My leadership roles in the Pediatric Brain Tumor Consortium and the Stanford Center for Childhood Brain Tumors have enabled me to translate discoveries from my laboratory to early phase clinical trials for children with DIPG and other gliomas affecting children, adolescents and young adults.
The nervous system regulates stem and precursor cell behavior across a range of tissues. 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. 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 proliferation and growth of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include 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. This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. NLGN3 is necessary for the growth of gliomas in a range of preclinical models, and therapeutic targeting of NLGN3 is presently under clinical investigation. 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.