Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring

Abstract

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