The Role of GABA Transaminase ABAT in Pediatric Brain Tumor Medulloblastoma Development and Spread - Medulloblastoma (MB), is the most common pediatric brain tumor originating in the GABA-rich cerebellum. 40% of MB patients present as both cerebellar and cerebral spinal fluid (CSF) leptomeningeal metastases which results in having dismal outcomes. The project’s long-term goal is to determine how MB become life-threatening leptomeningeal metastases by studying the tumor and brain microenvironment from a neurodevelopment and cancer neuroscience perspective. Although abnormal GABAergic receptor activation has been described in group 3 MB, no studies until ours recently had yet to elucidate the contribution of receptor-independent GABA metabolism to MB pathogenesis and metastasis. Overall, we were the first to identify GABA metabolic shunt enzyme GABA Transaminase (ABAT) expression is correlated with cerebellar development and is used by MB to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination. Specifically, we show proliferative MB cells at the primary cerebellar site have low ABAT. However, a sub-population of ABAT positive MB cells at the primary cerebellar site display neuron-like characteristics (including metabolism) and are the seeds of MB metastasis. In addition to being a GABA metabolic enzyme, we determined that expression of ABAT induces epigenetic modification by significantly reducing histone acetylation at the 4th lysine residue of the histone H3 protein (H3K4ac) and significantly increase in histone deacetylase activity. Furthermore, ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We found metastatic MB cells require ABAT to maintain viability in the metabolite-scarce CSF by using GABA through the GABA metabolic shunt as an energy source substitute, thereby facilitating leptomeningeal metastasis formation. Therefore, we hypothesize ABAT has a dual-biological role: lack of its expression during normal cerebellar development contributes to proliferation leading to group 3 medulloblastoma formation; While its overexpression after MB development results in tumor dormancy leading to survival benefit in disseminated cells in leptomeningeal metastasis. Utilizing foundations of neurobiology by using: a) human and mouse-derived neural stem cells, neurons and glial cells, b) unique strengths of patient-xenografts, c) BarTeL transgenic mice, d) novel small molecule ABAT inhibitor which crosses the blood-brain barrier, we will: 1st interrogate the role of ABAT in cerebellar neurodevelopment and Group 3 MB initiation, 2nd contribution of nuclear ABAT to transcription through histone acetylation modification in metastases, 3rd investigate ABAT as a potential therapeutic target for MB metastases. The current proposal will shed further light on understanding how metastatic MB cells develop and adapt to their neural niche opening avenues for novel therapeutic interventions for children that have this devastating disease.
