Glioma Circuitry: Bridging Systems Neuroscience and Cancer

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Project Summary DP1 NS111132 original summary: High-grade gliomas such as glioblastoma and diffuse intrinsic pontine glioma (DIPG) are among the most intractable human cancers. These tumors are quick to recur and nearly impossible to eliminate, and as such represent the leading cause brain cancer-related death in both children and adults. A fundamental shift in our approach to glioma therapy is in dire need. My research group has recently discovered that gliomas grow in response to nervous system activity (Venkatesh et al., 2015, Cell). We initially conceptualized this discovery in the framework of neuronal activity-regulated molecular factors released into the tumor microenvironment. While brain activity-regulated growth factor secretion is certainly part of the picture, it is insufficient to explain the striking magnitude of the effect, nor the apparent dependency of glioma on these neuronal mechanisms (Venkatesh et al., 2017, Nature). Our cellular and molecular work has led us to the startling realization that gliomas functionally integrate into electrically active neuronal circuits through bona fide neuron to glioma synapses, and the effects of neuron – glioma signaling may be amplified throughout the tumor via a network of recently described glioma to glioma gap junction-mediated connections (Osswald et al., 2015, Nature). We hypothesize that this cooperative interconnected network of glioma cells and neurons is fundamental to high- grade glioma progression and therapy resistance. Effective therapy for this lethal group of brain cancers may therefore require targeting not only molecular mechanisms of cell proliferation and survival, but also patterns of membrane depolarization and structural connections between cells. In order to study this, a shift from the predominant cellular/molecular perspective of cancer biology to a systems neuroscience approach is required.