We propose to study the role of key metabolic regulators, AMPK, PkM2 and Hk2 in cerebellar development and medulloblastoma pathogenesis. Medulloblastoma, the most common malignant brain tumor in children, arises as a disruption of postnatal brain growth. We have found that aerobic glycolysis is integral to the physiologic process of progenitor proliferation in the postnatal cerebellum, and that up-regulation of Hk2 and PkM2 is required for this metabolic pattern. Importantly, inducing medulloblastoma formation in transgenic mice leads to prolonged aerobic glycolysis and aberrant expression of Hk2 and PkM2. We have previously demonstrated that conditional genetic deletion of Hk2 in cerebellar progenitors inhibits medulloblastoma formation in a primary mouse tumor model. Our preliminary evidence implicates activation of AMPK as the mechanism that blocks tumor growth when Hk2 is deleted. In contrast to Hk2, however, we found that deleting PkM2 promoted rather than inhibited tumor growth. These data demonstrate the potential of metabolic modulation to treat medulloblastoma but also the need for additional mechanistic understanding to appropriately target therapy. We now propose in our Aims: 1. To determine if Hk2-dependent glycolysis functions to prevent AMPK-mediated growth suppression during cerebellar development and tumorigenesis. 2. To determine if PkM2 promotes developmental and malignant growth by channeling intermediate products of aerobic glycolysis for biosynthetic processes. 3. To determine, patient-derived medulloblastoma samples, if Hk2 and PkM2 configure the metabolism of human medulloblastoma to promote growth. Through these aims, we will gain new insight into how metabolic processes mediated by Hk2, AMPK and PkM2 combine to regulate postnatal neurogenesis, become co-opted in medulloblastoma, and may be targeted for novel therapies.
This project will investigate ways in which normal childhood brain growth is linked to medulloblastoma, the common malignant pediatric brain tumor. In normal brain growth, cells that divide to make more brain cells have special ways to process sugar molecules into energy. We think that medulloblastoma cells use this way of processing sugar molecules, and that this process itself may be targeted for new medulloblastoma treatment.
|Tech, Katherine; Tikunov, Andrey P; Farooq, Hamza et al. (2017) Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation. Cancer Res 77:3217-3230|
|Lang, Patrick Y; Nanjangud, Gouri J; Sokolsky-Papkov, Marina et al. (2016) ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation. Development 143:4038-4052|
|Crowther, Andrew J; Ocasio, Jennifer K; Fang, Fang et al. (2016) Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway. Cancer Res 76:3211-23|
|Williams, Scott E; Garcia, Idoia; Crowther, Andrew J et al. (2015) Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice. Development 142:3921-32|