Enhanced fatty acid oxidation provides glioblastoma cells metabolic plasticity to accommodate to its dynamic nutrient microenvironment

Abstract

Despite advances in molecularly characterizing glioblastoma (GBM), metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analysis coupling global metabolomic and gene expression profiling on patient-derived glioma identified fatty acid β-oxidation (FAO) as a metabolic node in GBM. We determined that the biologic consequence of enhanced FAO is directly dependent upon tumor microenvironment. FAO serves as a metabolic cue to drive proliferation in a β-HB/GPR109A dependent autocrine manner in nutrient favorable conditions, while providing an efficient, alternate source of ATP only in nutrient unfavorable conditions. Rational combinatorial strategies designed to target these dynamic roles FAO plays in gliomagenesis resulted in necroptosis-mediated metabolic synthetic lethality in GBM. In summary, we identified FAO as a dominant metabolic node in GBM that provides metabolic plasticity, allowing these cells to adapt to their dynamic microenvironment. Combinatorial strategies designed to target these diverse roles FAO plays in gliomagenesis offers therapeutic potential in GBM.

Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy

“…However, our current study suggests that under physiologically relevant glucose conditions (2.5 mM), FAs play a central role in the overall GBM metabolome regardless of mutational status. A study published during revision of the current manuscript found a difference in use of FAO in tumors based on TGCA classification ( Kant et al., 2020 ). Specifically, FAO was found to be enhanced in mesenchymal tumor lines.…”

Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

“…For the synthesis of ATP, a thorough metabolic rewiring occurs in IDH1 mt cells, leading to a vast increase in the number of mitochondria as was shown in oligodendroglioma cells [ 49 ]. IDH1 wt glioblastoma cells mainly use glycolysis as a classical Warburg phenotype that produces lactate [ 50 , 51 ], whereas IDH1 mt secondary glioblastoma use OXPHOS for the generation of ATP using pyruvate and glutamate, which has been determined at the gene expression, protein, and metabolite levels [ 42 , 45 , 52 , 53 , 54 , 55 ].…”

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

“…Furthermore, in vivo studies have also demonstrated that the activation of HCAR2, with niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis [86,87], while deletion of HCAR2 increased tumor incidence of spontaneous breast cancer in transgenic mice [83]. In contrast to data reported in colon and breast cancer, a recent study shows an increased proliferation of cells from glioblastoma by the activation of HCAR2 with butyrate [88]. A better knowledge of the specific tissue-conditioning factors of cancer is warranted to understand these discrepancies.…”