PROJECT SUMMARY Malignant gliomas are a group of high-grade brain neoplasms that represent the most common form of malignant brain tumors. Current treatment regimens include an amalgamation of surgical, chemotherapeutic and radiation treatments yet median survival for the most lethal glioma variant, glioblastoma multiforme (GBM) remains stagnant at a mere 15 months post-diagnosis. While new scientific inquiries continue to yield novel disease-driving mechanisms, survival rates have remained unchanged over the past 30 years, highlighting a need for new therapeutic approaches for these uniformly fatal diseases. The existence of developmental paradigms in cancer biology has long been established as a source of dysregulated biological processes that facilitate tumor progression. In addition to developmental biology approaches in cancer research, recent scientific investigations have revealed that malignant gliomas form direct synaptic electrochemical connections with extratumoral neurons in order to sustain continued proliferation and migration. The study of this complex interplay between glioma cells and non-tumor neural cells has launched a new line of scientific inquiry known as “cancer neuroscience”. Given the existence of both of these developmental and neuroscientific precedents, we propose to investigate how developmental programs responsible for synaptogenesis and synaptic maintenance are utilized and sustained in malignant glioma. Our laboratory has identified a novel membrane-bound protein, immunoglobulin superfamily member 3 (IGSF3), with high expression levels in both in utero neurodevelopment and malignant glioma. Previous studies have shown that IGSF3 controls neuronal morphogenesis in the developing brain and our preliminary data suggests it may serve as a novel fetal oncogene with markedly increased expression in both development and malignant glioma but minimal expression in the postnatal brain. Our preliminary studies using an in utero electroporation mouse model of glioma have revealed that IGSF3 overexpression drives tumor progression by increasing proliferation and decreasing survival. Furthermore, overexpression of IGSF3 promotes early-onset seizures in tumor mice and selectively increases excitatory presynaptic and postsynaptic components at the tumor margin. Based on our initial studies, we have hypothesized that increased IGSF3 drives progression of malignant glioma by disrupting the synaptic microenvironment and increasing hyperexcitability in the surrounding neuronal circuitry. This hyperexcitability then feeds back to the tumor to promote tumor progression through increased mitogenic and promigratory signaling pathways. Herein, our research proposal seeks to summarize previously reported research findings and our preliminary experimental results that support our hypothesis and rationale, and aims to explain the significance and innovation of our study as well as the scientific methodologies and techniques we will utiliz...