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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.
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Details
1 Beaumont Health, Department of Radiation Oncology, Royal Oak, USA (GRID:grid.461921.9) (ISNI:0000 0004 0460 1081)
2 Beaumont Health, Department of Metabolomics and Obstetrics/Gynecology, Beaumont Research Institute, Royal Oak, USA (GRID:grid.461921.9) (ISNI:0000 0004 0460 1081)
3 University of Alabama at Birmingham, Department of Neurosurgery, Alabama, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
4 Beaumont Health, Department of Radiation Oncology, Royal Oak, USA (GRID:grid.461921.9) (ISNI:0000 0004 0460 1081); Oakland University William Beaumont School of Medicine, Royal Oak, USA (GRID:grid.261277.7) (ISNI:0000 0001 2219 916X)