American Association for Cancer Research
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Figure S4 from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring

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journal contribution
posted on 2023-05-25, 16:00 authored by Jean Nakhle, Khattar Khattar, Tülin Özkan, Adel Boughlita, Daouda Abba Moussa, Amelie Darlix, Frédérique Lorcy, Valérie RIGAU, Luc BAUCHET, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Floriant Bellvert, Laurent Turchi, Thierry Virolle, Jean-Philippe Hugnot, Nicolas Buisine, Mireille Galloni, Valerie Dardalhon, Anne-Marie Rodriguez, Marie-Luce Vignais

Metabolites produced by GSCs following MSC mitochondria acquisition and TMZ treatment



Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSCs), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSCs) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the TCA cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.