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

Journal Article (2017)
Author(s)

Elias A. El-Habr (UPMC-Sorbonne Universités & CNRS)

Luiz G. Dubois (Secretaria de Estado de Saúde do Rio de Janeiro/RJ, UPMC-Sorbonne Universités & CNRS)

Fanny Burel-Vandenbos (Université de Nice-Sophia Antipolis)

Alexandra Bogeas (UPMC-Sorbonne Universités & CNRS)

Joanna Lipecka (UPMC-Sorbonne Universités & CNRS, Paris Descartes University)

Laurent Turchi (Inserm U1091)

François Xavier Lejeune (UPMC-Sorbonne Universités & CNRS)

Paulo Lucas Cerqueira Coehlo (UPMC-Sorbonne Universités & CNRS)

Tomohiro Yamaki (ENS-PSL Research University & CNRS)

Bryan M. Wittmann (Metabolon, Inc.)

Mohamed Fareh (Université de Nice-Sophia Antipolis, TU Delft - BN/Chirlmin Joo Lab, Kavli institute of nanoscience Delft)

Emna Mahfoudhi (Institut Gustave Roussy)

Maxime Janin (Paris Descartes University)

Ashwin Narayanan (UPMC-Sorbonne Universités & CNRS)

Ghislaine Morvan-Dubois (UPMC-Sorbonne Universités & CNRS)

Charlotte Schmitt (UPMC-Sorbonne Universités & CNRS)

Maité Verreault (UPMC-Sorbonne Universités & CNRS)

Lisa Oliver (Université de Nantes)

Ariane Sharif (School of Medicine)

Johan Pallud (Paris Descartes University)

Bertrand Devaux (UPMC-Sorbonne Universités & CNRS, Paris Descartes University)

Stéphanie Puget (Necker-Enfants Malades Hospital)

Penelope Korkolopoulou (National and Capodistrian University of Athens)

Pascale Varlet (Paris Descartes University)

Chris Ottolenghi (Paris Descartes University)

Isabelle Plo (Institut Gustave Roussy)

Vivaldo Moura-Neto (Secretaria de Estado de Saúde do Rio de Janeiro/RJ)

Thierry Virolle (Université de Nice-Sophia Antipolis)

Hervé Chneiweiss (UPMC-Sorbonne Universités & CNRS)

Marie Pierre Junier (UPMC-Sorbonne Universités & CNRS)

Research Group
BN/Chirlmin Joo Lab
Copyright
© 2017 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, M. 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
DOI related publication
https://doi.org/10.1007/s00401-016-1659-5
More Info
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Publication Year
2017
Language
English
Copyright
© 2017 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, M. 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
Research Group
BN/Chirlmin Joo Lab
Issue number
4
Volume number
133
Pages (from-to)
645-660
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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.