The long term objective of this proposal is to improve the therapy of glioma by better understanding the role altered metabolism plays in gliomagenesis. Two metabolic enzymes, hexokinase (HK) and pyruvate kinase (PK) are key regulators of the metabolic changes that accompany tumorigenesis. Normal cells express the HK1 and PKM1 isoforms and preferentially use glucose for ATP generation while gliomas, in contrast, express HK2 and PKM2 and use glucose to synthesize macromolecules needed for proliferation. Glial tumors, however, don't arise from differentiated cells but from progenitor cels which express low levels of all HK and PKM isoforms. Gliomagenesis may therefore not be driven by a simple switch from HK1/PKM1 to HK2/PKM2 expression but rather by metabolic enzyme-related changes that favor aberrant vs normal differentiation in progenitor cell populations. It is not known how HK and PKM expression changes along differentiation pathways, what drives these changes, or how important these shifts are to normal cell fate decisions and gliomagenesis. We have shown, however, that oligodendrocyte precursor cells (OPCs) initiate cell fate decisions by segregating NG2 to self-renewing daughter cells, and TRIM32, a ubiquitin ligase for c-myc, to progeny destined for differentiation. Malignant OPCs in contrast generate progeny that symmetrically express NG2/EGFR, fail to express TRIM32 or differentiate, and give rise to oligodendroglioma. Because NG2 and TRIM32 both have the potential to regulate metabolic enzyme expression, we hypothesize that HK- and PKM- related parameters change along cell fate pathways, and that control of these events by the cell fate determinants NG2 and TRIM32 drive normal cell fate decisions, and in aberrant cases, contribute to gliomagenesis. This hypothesis will be tested by 1) defining how metabolic enzyme expression and metabolism change along normal and malignant OPC fate pathways, 2) determining if NG2 and/or TRIM32 regulate HK or PKM expression and metabolism in OPCs, and 3) determining if HK- or PKM-related events control OPC metabolism and cell fate decisions, and in doing so contribute to gliomagenesis.
If successful, the work will represent a paradigm shift in the way we view how pyruvate kinase regulates the metabolic processes that contribute to cancer, and will identify new therapeutic targets for modulation of the cell fate decision that underlie brain tumor formation.
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