598 antagonizing, not stimulating, PPARc would have a prac- tical therapeutic use in MBs. Indeed, inhibiting PPARc was markedly beneﬁcial in counteracting hyperproliferation, reducing tumor burden, and extending the survival of Shh- driven MBs in mice (Fig. 6). Of note, when examined for their PPARc expression using tissue microarrays, marked PPARc staining was detected in [50 % of the Shh sub- group (Supplementary data). Intriguingly high PPARc staining was also present in other groups and prevalent in Group D samples. While more elaborate analysis (includ- ing demographic, gender, survival) in larger cohorts is needed to understand the role and function of PPARc in human tumors, deregulation of this pathway appears to be widespread in human MB. The aforementioned role for the E2F1 ? PPARc axis as a potent effector of hedgehog signaling in modulating the glycolytic index has also numerous implications. In addi- tion to presenting a viable therapeutic avenue in this pediatric brain tumor, it helps explain tumor etiologies associated with hedgehog and/or Rb/E2F deregulation. Elevated glucose uptake and hexokinase II activity have been characteristic features correlated with poor prognosis in a wide spectrum of malignancies. These features are routinely exploited in diagnostic imaging techniques like ﬂuorodeoxyglucose (FDG)-positron emission tomography [13]. Yet, a sizable number of human cancers are also FDG- negative and a gradation of glycolic indices is reported within many tumor types that may or may not reﬂect spe- ciﬁc lesions. Some positive regulators of cell proliferation are associated with reduced hexokinase activities and diminished glycolysis. For instance, antisense-mediated cyclin D1 down-modulation has been shown to upregulate glycolysis in vivo, by releasing hexokinase II from inhibi- tion [38]. These contradictions perhaps reﬂect the intricacies underlying the cancer-associated metabolic networks and their confounding heterogeneity. In medul- loblastoma, a unique, albeit more deﬁned, metabolic pattern controlled by Shh is beginning to emerge: The striking accumulation of lipid droplets we describe earlier ([2] and Fig. 1a), is matched by the equally striking glycolytic index and conﬁrmed by elevated FDG-PET activity. This phe- notype is consistent with substrate utilization patterns in highly anabolic tissues where excessive glucose uptake is routed to fat production and excessive lipogenesis. More- over, this particular substrate utilization pattern in shh- driven MBs unravels a new circuitry coupling hedgehog signaling directly to glucose uptake. At the heart of this process is the Rb/E2F complex, itself the target of growth factors and external trophic signals and a tumor suppressor broadly inactivated in human cancers. Our work identiﬁed the (Shh a Rb a E2F1 ? PPAR) axis as a functional metabolic driver of medulloblastoma tumor formation and the core of its nutrient sensing network coupling external 123 Acta Neuropathol (2012) 123:587–600 dietary conditions to the metabolic adaptation of the cellular milieu, including the regulation of the glycolic index. We note that in CGNPs, the mere incubation of primary cells with Shh markedly triggers Glut4—a glucose transporter typically induced with insulin stimulation. As such, glucose utilization in neural precursors could be primarily a Shh- regulated event, irrespective of hormonal status. Indeed, our data implicate this E2F1-dependent glycolytic process as a systematic, distinctly cell-autonomous process that is medi- ated by PPARc but triggered by Shh in medulloblastoma. Acknowledgments This Study is supported by funding from the Qatar Foundation, Qatar National Research Fund (Z.N, NPRP 09-413-3-104) and the NINDS (A.M.K R01 NS061070). 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