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

Elias El-Habr 1 Gustavo Luiz Dubois 2, 1 Fanny Burel-Vandenbos 3, 4 Alexandra Bogeas 1 Joanna Lipecka 1, 5 Laurent Turchi 3 François-Xavier Lejeune 6 Paulo Lucas Cerqueira Coelho 1 Kunihiko Yamaki 1 Bryan Wittmann 7 Mohamed Fareh 3 Emna Mahfoudhi 8 Maxime Janin 9, 10 Ashwin Narayanan 1 Ghislaine Morvan-Dubois 1 Charlotte Schmitt 11 Maïté Verreault 11 Lisa Oliver 12 Ariane Sharif 13 Johan Pallud 14 Bertrand Devaux 1, 14 Stéphanie Puget 15 Penelope Korkolopoulou 16 Pascale Varlet 17 Chris Ottolenghi 10, 9 Isabelle Plo 18 Vivaldo Moura-Neto 2 Thierry Virolle 4 Hervé Chneiweiss 1, * Marie-Pierre Junier 1, *
Abstract : 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.
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Acta Neuropathologica, Springer Verlag, 2016, 133 (4), pp.645-660. 〈10.1007/s00401-016-1659-5〉
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Elias El-Habr, Gustavo Luiz Dubois, Fanny Burel-Vandenbos, Alexandra Bogeas, Joanna Lipecka, et al.. A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. Acta Neuropathologica, Springer Verlag, 2016, 133 (4), pp.645-660. 〈10.1007/s00401-016-1659-5〉. 〈inserm-01481051〉

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