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

Elias El-Habr; Gustavo Luiz Dubois; Fanny Burel-Vandenbos; Alexandra Bogeas; Joanna Lipecka; Laurent Turchi; François-Xavier Lejeune; Paulo Lucas Cerqueira Coelho; Kunihiko Yamaki; Bryan Wittmann; Mohamed Fareh; Emna Mahfoudhi; Maxime Janin; Ashwin Narayanan; Ghislaine Morvan-Dubois; Charlotte Schmitt; Maïté Verreault; Lisa Oliver; Ariane Sharif; Johan Pallud; Bertrand Devaux; Stéphanie Puget; Penelope Korkolopoulou; Pascale Varlet; Chris Ottolenghi; Isabelle Plo; Vivaldo Moura-Neto; Thierry Virolle; Hervé Chneiweiss; Marie-Pierre Junier

doi:10.1007/s00401-016-1659-5

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, *}

* Auteur correspondant

1 NPS - Neuroscience Paris Seine

2 Instituto Estadual do cerebro Paulo Niemeyer

3 IBV - Institut de Biologie Valrose

4 Service de pathologie

5 CPN - U894 - Centre de Psychiatrie et Neurosciences

6 B2A - Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing

7 Metabolon

8 Hématopoïèse normale et pathologique

9 CHU Necker - Enfants Malades [AP-HP]

10 Service de biochimie métabolique [CHU Necker]

11 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute

12 CRCNA - Centre de Recherche en Cancérologie / Nantes - Angers

13 Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer

14 UPD5 - Université Paris Descartes - Paris 5

15 Department of Paediatric Neurosurgery, Necker Enfants Malades Hospital, Paris, France.

16 Department of Haematopathology

17 Service de neuropathologie

18 U1170 Inserm - Hématopoïèse normale et pathologique

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.

Type de document :

Article dans une revue

Acta Neuropathologica, Springer Verlag, 2016, 133 (4), pp.645-660. 〈10.1007/s00401-016-1659-5〉

Domaine :

Sciences du Vivant [q-bio] / Cancer

Liste complète des métadonnées

http://www.hal.inserm.fr/inserm-01481051
Contributeur : Elizabeth Bernardo <>
Soumis le : jeudi 2 mars 2017 - 10:47:59
Dernière modification le : jeudi 20 septembre 2018 - 17:02:01

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

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

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