A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma

• Published in: Acta neuropathologica 2017-04, Vol.133 (4), p.645-660
• Main Authors: El-Habr, Elias A., Dubois, Luiz G., Burel-Vandenbos, Fanny, Bogeas, Alexandra, Lipecka, Joanna, Turchi, Laurent, Lejeune, François-Xavier, Coehlo, Paulo Lucas Cerqueira, Yamaki, Tomohiro, Wittmann, Bryan M., Fareh, Mohamed, Mahfoudhi, Emna, Janin, Maxime, Narayanan, Ashwin, Morvan-Dubois, Ghislaine, Schmitt, Charlotte, Verreault, Maité, Oliver, Lisa, Sharif, Ariane, Pallud, Johan, Devaux, Bertrand, Puget, Stéphanie, Korkolopoulou, Penelope, Varlet, Pascale, Ottolenghi, Chris, Plo, Isabelle, Moura-Neto, Vivaldo, Virolle, Thierry, Chneiweiss, Hervé, Junier, Marie-Pierre
• Format: Article
• Language: English
• Subjects: Aged; Animals; Brain - metabolism; Brain - pathology; Brain - surgery; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - surgery; Cancer; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Death - physiology; Cell Proliferation - physiology; Child; Child, Preschool; Colleges & universities; Female; GABA; Gamma hydroxybutyrate; gamma-Aminobutyric Acid - metabolism; Glioma - metabolism; Glioma - pathology; Glioma - surgery; Gliomas; Humans; Hydroxybutyrates - metabolism; Life Sciences; Male; Medicine; Medicine & Public Health; Metabolism; Metabolites; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neurosciences; Original Paper; Pathology; Stem cells; Succinate-Semialdehyde Dehydrogenase - metabolism; Tumors
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-016-1659-5

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 α-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/α-ketoglutarate 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.