PM-06 * DIFFERENTIAL SPLICING OF PYRUVATE KINASE REGULATES PROGENITOR CELL CYCLE AND MEDULLOBLASTOMA TUMORIGENESIS

Abstract

BACKGROUND: We have previously shown that aerobic glycolysis, a hallmark of cancer metabolism, plays a physiological role in postnatal neurogenesis and is co-opted in medulloblastoma. Medulloblastoma, the most common malignant brain tumor in children, arises from cerebellar progenitors that normally proliferate in the first year of life then exit the cell cycle. Processes that regulate the developmental proliferation of neural progenitors may facilitate tumorigenesis when activated aberrantly. We have identified Pyruvate kinase isoform M2 (PKM2) as a developmentally-regulated enzyme that accelerates medulloblastoma tumorigenesis in a mouse model and is a potential target for novel cancer therapies. METHODS: We examined metabolism and proliferation in mice with and without a conditional deletion of PkM2 using NMR-based metabolomics, immunohistochemistry and Western blot. We examined the importance of PkM2 in medulloblastoma tumorigenesis by analyzing the survival of medulloblastoma-prone ND2: SmoA1 mice with and without PkM2 deletion. RESULTS: Brain progenitors specifically splice the PkM gene into the less catalytically active PkM2 isoform, while differentiated neurons uniformly express the constituently active isoform PkM1. Deletion of PkM2 altered energy metabolism, reducing lactic acid production and increasing glutamine consumption. Despite reduced aerobic glycolysis, PkM2-deleted progenitors proliferated more rapidly. In tumor-prone mice, PkM2 deletion accelerated medulloblastoma tumorigenesis and shortened survival. CONCLUSIONS: Our findings of increased tumorigenesis in PkM2-deleted mice demonstrate that PkM2 activity is not required for tumor formation. Further, the generation of lactic acid, per se, does not enhance tumorigenesis. Rather, we propose that PkM2 functions as a less active Pyruvate Kinase isozyme that channels glycolytic intermediates into alternative metabolic fates to support proliferation. Accordingly, splicing PkM into the PkM2 isoform reduces PkM activity in progenitors, and PkM2 deletion enhances this phenotype, accelerating tumor formation in ND2:SmoA1 mice. Strategies that increase PkM2 enzymatic activity may conversely inhibit medulloblastoma growth, providing a novel, metabolic approach to anti-tumor therapy.