Spatial Mapping of Malignant Subpopulations Enabling Neuron-Glioma Circuit Interactions in DIPG

Key Words: Cancer Neuroscience; Pediatric Glioma; DIPG; Microenvironment; Neural circuit connectivity; Malignant networks; Spatial Mapping; Electrophysiology; MERFISH

Diffuse intrinsic pontine glioma (DIPG) is amongst the most lethal types of childhood cancer. Due to its limited occurrence, DIPG is often not prioritized in research. For these cancers, surgical resection is not an option due to the diffuse infiltration of tumor cells into the surrounding normal brain, creating a major limitation to treatment. Thus, defining how these malignant cells interact with their microenvironment is crucial to understanding the fundamental factors contributing to this disease pathology. My past work has illustrated that one critical microenvironmental dependency of DIPG cells is their direct integration into neuronal circuitry via neuron-to-glioma synapses. We have found that neuronal activity promotes DIPG progression, which highlights the previously unexplored potential to target neuron-glioma circuit dynamics for therapy of these lethal cancers. By appreciating these paradigm-shifting insights, this proposal seeks to uncover the detailed mechanisms by which DIPGs rely upon these powerful interactions for progression and may uncover innovative angles for therapeutic strategies. Using novel imaging and neuroscience tools uniquely applied in the context of cancer, this proposal aims to further clarify the electrophysiological profiles and spatiotemporal expression patterns of neurophysiological genes that enable these neuron-glioma interactions within distinct malignant subpopulations over the course of disease progression. We will then further functionally test the requirement of specific neurophysiological genes by using genetic manipulation and pharmacological inhibition techniques to target specific ion channels of interest. The proposed studies will investigate a completely novel vulnerability of DIPG, its neurophysiologic component, to elucidate how deeply integrated malignant cells are into neighboring neural networks and to understand how these microenvironmental dependencies can be targeted for treatment of this disease. Overall, we will answer fundamental questions in this emerging field of the neural regulation of cancers with the potential to change the way we treat this devastating group of cancers.