Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination.
Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination.
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DOI：
10.1016/j.celrep.2021.109302
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发表时间：
2021-06-29
期刊：
影响因子：
8.8
通讯作者：
Neman J
中科院分区：
文献类型：
--
作者：
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
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. Through the lens of developmental neurobiology, Martirosian et al. interrogate the mechanisms promoting medulloblastoma metastasis. They identify a pathway correlated with metabolic and histone characteristics in both differentiated neural cells and medulloblastoma and show how this pathway can be exploited by disseminated medulloblastoma cells to form leptomeningeal metastases.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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Schultz N
DOI：
10.1126/science.aaz2193
发表时间：
2020-07-17
期刊：
Science (New York, N.Y.)
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ALMEFTY, O
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