Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin

Abstract

Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. BTICs of different subtypes were challenged with oxidative phosphorylation (OXPHOS) inhibition with metformin to assess the differential effects of metabolic intervention on key resistance features. Whereas mesenchymal BTICs varied according to their invasiveness, they were in general more glycolytic and less responsive to metformin. Proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathway, and responded better to metformin. Targeting glycolysis may be a promising approach to inhibit tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors.

Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells

“…In a previous study [ 7 ], we described the metabolic preferences of proneural and mesenchymal BTICs and their response to the metabolic drug metformin. For that purpose, we performed glucose flux analyses, which demonstrated that mesenchymal BTICs are more glycolytic while proneural BTICs metabolize glucose more towards the pentose phosphate pathway.…”

“…One of the pathophysiological features of GB is aberrant tumor metabolism [ 5 ]. Whereas glucose metabolism has been extensively explored [ 6 , 7 ], there is still limited data on amino acid metabolism. In our previous work, we were able to demonstrate the metabolic preferences of distinct metabolic subtypes of glioma.…”

“…In our previous work, we were able to demonstrate the metabolic preferences of distinct metabolic subtypes of glioma. We found mesenchymal BTICs to be more glycolytic, whereas proneural BTICs catabolize glucose more towards the pentose phosphate pathway [ 7 ]. GBs also use amino acids such as glutamine to meet their energetic needs, especially when glucose availability is limited [ 8 ].…”

“…Metformin is an oral hypoglycemic agent that is under investigation as a potential antineoplastic agent [ 12 ]. Metformin has been found to inhibit proliferation and migration of BTICs, especially of the proneural subtype, by altering glucose metabolism in a subtype-specific way [ 7 ]. Whereas glucose metabolism and respiration under treatment with metformin have been extensively studied in glioma [ 7 , 13 ], though with partly contradictory results, little is known about the effects of metformin on amino acid metabolism.…”

“…Metformin has been found to inhibit proliferation and migration of BTICs, especially of the proneural subtype, by altering glucose metabolism in a subtype-specific way [ 7 ]. Whereas glucose metabolism and respiration under treatment with metformin have been extensively studied in glioma [ 7 , 13 ], though with partly contradictory results, little is known about the effects of metformin on amino acid metabolism. However, a better understanding of the holistic landscape of glucose and amino acid metabolism in GB is crucial for the development of novel therapeutic strategies and may help to understand resistance to current treatment options, with potential translation into clinical applications.…”