Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination Journal Article
| Authors: | Martirosian, V.; Deshpande, K.; Zhou, H.; Shen, K.; Smith, K.; Northcott, P.; Lin, M.; Stepanosyan, V.; Das, D.; Remsik, J.; Isakov, D.; Boire, A.; De Feyter, H.; Hurth, K.; Li, S.; Wiemels, J.; Nakamura, B.; Shao, L.; Danilov, C.; Chen, T.; Neman, J. |
| Article Title: | Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination |
| Abstract: | Medulloblastoma (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. © 2021 The Authors |
| Keywords: | controlled study; protein expression; human cell; nonhuman; mouse; animal tissue; cell viability; cerebellum; gene; metastasis; gene expression; protein degradation; protein metabolism; sonic hedgehog protein; animal experiment; animal model; cerebrospinal fluid; histone; gabaergic system; medulloblastoma; upregulation; tumor growth; meningeal cyst; wnt protein; oxidative phosphorylation; tumor microenvironment; leptomeningeal disease; tumor dormancy; energy resource; 4 aminobutyrate aminotransferase; human; female; article; medulloblastoma cell line; abat; gaba shunt; abat gene |
| Journal Title: | Cell Reports |
| Volume: | 35 |
| Issue: | 13 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2021-06-29 |
| Start Page: | 109302 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2021.109302 |
| PUBMED: | 34192534 |
| PROVIDER: | scopus |
| PMCID: | PMC8848833 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2021 -- Source: Scopus |
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