期刊
ACTA NEUROPATHOLOGICA
卷 133, 期 4, 页码 645-660出版社
SPRINGER
DOI: 10.1007/s00401-016-1659-5
关键词
Brain cancer; DIPG; Cancer stem cell; ALDH5A1; GABA; 5-hmC; Valproate
资金
- La Ligue nationale contre le cancer (Equipe Labellisee LIGUE, Equipe Labelisee LIGUE HC/MPJ)
- Institut National du Cancer [INCa 2012-1-PLBIO-07-INSERM-1, HC/MPJ]
- Canceropole Region Ile-de-France
- CAPES/COFECUB (Coordination pour le perfectionnement du personnel de l'enseignement superieur/Comite francais d'evaluation de la cooperation universitaire et scientifique avec le Brasil)
- Fundacao Ary Frauzino para o Cancer
- Neurosurgeon college of Chiba prefecture, Japan
Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting a-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/aketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.
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