Pyruvate carboxylation identifies Glioblastoma Stem-like Cells opening new metabolic strategy to prevent tumor recurrence

Abstract: Glioblastoma (GBM) are currently associated with a dismal prognosis due to therapeutic resistance. Within the diverse tumor subpopulations, Glioblastoma Stem-like Cells (GSC) have been involved in GBM recurrence. In our study, we demonstrated that these tumor cells can be identified through singular mitochondrial alternative metabolisms. Combining state-of-the-art metabolic studies and the development of a straightforward tumoroid model recapitulating key features of primary GBM cultures, we uncovered a significant use of a-ketoglutarate reductive carboxylation and pyruvate carboxylation in tumoroid GBM cells, catalyzed respectively by isocitrate dehydrogenase and pyruvate carboxylase enzymes. We demonstrated that these singular metabolic features are shared by GBM cells from the mesenchymal subtype and radiation-escaping cells, also involved in recurrence. Finally, we demonstrated that pyruvate carboxylation is required for GBM cell survival in hypoxic niches where glutamine is restricted. Thus, besides providing a new way to identify GSC, our study also opens new therapeutic strategy to limit GBM recurrence.