Figure 2.

Tumor microenvironment and molecular signature, 2 drivers of GSCs metabolic phenotype. GSCs reside in singular tumor microenvironment in GBM called the perivascular and the hypoxic niche. Each niche is associated with specific molecular signature and metabolic phenotype. The perivascular GSCs display a PN signature and a strong glycolytic metabolism mainly based on blood glucose. In these cells, glucose can be directly converted to lactate or oxidized within the mitochondria through OXPHOS. Furthermore, these cells highly express GS allowing the direct synthesis and secretion of glutamine within the TME. In contrast, hypoxic GSCs usually belong to the mesenchymal subtype and do not express GS. These cells are residing in a harsher environment display flexible metabolism fueled by lactate, ketone bodies, amino acids, including glutamine, released in the microenvironment by other cancer cells and/or stromal cells including astrocytes or cancer-associated fibroblasts. In absence of O2, these substrates supply a truncated TCA cycle allowing the generation of energy and biosynthetic precursors such as lipids or nucleic acids, as well as antioxidant glutathione synthesis. CAF, Cancer-associated fibroblast; GBM, Glioblastoma; GSCs, Glioblastoma stem-like cells, GS, Glutamine synthetase; αKG, Alpha-ketoglutarate; KB, Ketone bodies; MES, Mesenchymal; OXPHOS, Mitochondrial oxidative phosphorylation; PN, Proneural; TCA, Tricarboxylic acid cycle.