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PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

Géraldine Gentric 1, * Yann Kieffer 1 Virginie Mieulet 1 Oumou Goundiam 1 Claire Bonneau 1 Fariba Nemati 2, 3 Ilse Hurbain 2, 3 G Raposo 2, 3 Tatiana Popova 1 Marc-Henri Stern 1 Valérie Lallemand-Breitenbach 4 Sebastian Müller 5 Tatiana Cañeque 5 Raphaël Rodriguez 5 Anne Vincent-Salomon 2 Hugues de Thé 4 Rodrigue Rossignol 6 Fatima Mechta-Grigoriou 1, *
* Corresponding author
1 U830 - Unité de génétique et biologie des cancers
2 Institut Curie
3 OPTeN (UMR_S_1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
4 GenCellDi (UMR_S_944) - Génomes, biologie cellulaire et thérapeutiques
5 CBMCT - UMR 3666 / U1143 - Chimie biologique des membranes et ciblage thérapeutique
6 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
Abstract : High-grade serous ovarian cancer (HGSOC) re- mains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogene- ity in HGSOC. By combining proteomic, metabo- lomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic meta- bolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1a axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1a. Active PGC-1a increases synthesis of electron trans- port chain complexes, thereby promoting mito- chondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conven- tional chemotherapies, in which increased oxida- tive stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1a-dependent mecha- nism that promotes OXPHOS metabolism and che- mosensitivity in ovarian cancer.
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Submitted on : Friday, January 24, 2020 - 12:57:09 PM
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Géraldine Gentric, Yann Kieffer, Virginie Mieulet, Oumou Goundiam, Claire Bonneau, et al.. PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metabolism, Elsevier, 2019, 29 (1), pp.156-173. ⟨10.1016/j.cmet.2018.09.002⟩. ⟨inserm-02454287⟩

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