Abstract
SUMMARYMedulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum. However, less aggressive WNT and SHH subtypes express higher ABAT levels compared with metastatic G3 and G4 tumors. We show that elevated ABAT expression results in increased GABA catabolism, decreased tumor cell proliferation, and induction of metabolic and histone characteristics mirroring GABAergic neurons. Our studies suggest ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We find metastatic MB cells require ABAT to maintain viability in the metabolite-scarce cerebrospinal fluid by using GABA as an energy source substitute, thereby facilitating leptomeningeal metastasis formation.
Highlights
Central nervous system (CNS) malignancies are the most frequent form of solid tumors in pediatric patients (Ostrom et al, 2018) and remain the leading cause of cancer-related mortality in children (de Blank et al, 2015)
ABAT is localized in GABAergic neural cell mitochondria and is associated with a differentiated phenotype To study how transdisciplinary investigation between neuroscience and cancer foundation can advance our understanding of MB, we sought to assess ABAT expression dynamics throughout neurodevelopment
A sudden increase and subsequent decrease in ABAT is seen during the embryonic day (E) 11.5 to E13.5 developmental period, which coincides with the cerebellar development phase containing the highest proportion of reported GABAergic progenitors (Carter et al, 2018; Butts et al, 2014)
Summary
Central nervous system (CNS) malignancies are the most frequent form of solid tumors in pediatric patients (Ostrom et al, 2018) and remain the leading cause of cancer-related mortality in children (de Blank et al, 2015). Medulloblastoma (MB) is the most common of these neoplasms, presenting as an aggressive heterogeneous cerebellar lesion. The focus has shifted to analyzing MB formation through the scope of cerebellar development, with evidence showing that cerebellar development and MB tumorigenesis share a common genetic ancestry (Roussel and Hatten, 2011; Schu€ller et al, 2008; Yang et al, 2008). Studies have elucidated how obstruction in neurodevelopmental programs gives rise to pediatric brain tumors (Jessa et al, 2019), and the transcriptional profile of these neoplasms mirrors those seen at specific time points of cerebellar development (Vladoiu et al, 2019). Cerebellar development can be used as a guide to discern the aberrant mechanisms in MB pathogenesis
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