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Open Access 01-04-2017 | Original Paper

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

Authors: Elias A. El-Habr, Luiz G. Dubois, Fanny Burel-Vandenbos, Alexandra Bogeas, Joanna Lipecka, Laurent Turchi, François-Xavier Lejeune, Paulo Lucas Cerqueira Coehlo, Tomohiro Yamaki, Bryan M. Wittmann, Mohamed Fareh, Emna Mahfoudhi, Maxime Janin, Ashwin Narayanan, Ghislaine Morvan-Dubois, Charlotte Schmitt, Maité 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

Published in: Acta Neuropathologica | Issue 4/2017

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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Title: A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma
Authors: Elias A. El-Habr
Luiz G. Dubois
Fanny Burel-Vandenbos
Alexandra Bogeas
Joanna Lipecka
Laurent Turchi
François-Xavier Lejeune
Paulo Lucas Cerqueira Coehlo
Tomohiro Yamaki
Bryan M. Wittmann
Mohamed Fareh
Emna Mahfoudhi
Maxime Janin
Ashwin Narayanan
Ghislaine Morvan-Dubois
Charlotte Schmitt
Maité 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
Publication date: 01-04-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1659-5

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

Abstract

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Abstract

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