Acta Neuropathol (2012) 123:587–600 parallel pathway to FASN. GW9662 treatment also reduced levels of glycolytic markers and cyclin D2 protein, but had no effect on HKI, in keeping with our in vitro results in CGNPs. When tested in the pzp53 MB cell line, GW9662 treatment was very effective in killing cancer cells in a dose-dependent manner (Fig. 5c), as show by a luminescence viability assay (Cell Titer-Glo). Using FDG-PET analysis, we observed a striking reduction in glucose uptake in GW9662-treated mice (Fig. 6a). This correlates with a functional effect of PPARc inhibition on de novo lipid synthesis (Fig. 6b). Finally, we Fig. 6 Treatment of medulloblastoma-bearing mice with PPARc antagonist GW9662 prolongs survival and reduces glucose uptake in vivo. a FDG-PET scan of medulloblastoma-bearing NeuroD2-SmoA1 mouse before and after treatment with the PPARc antagonist GW9662 (10 mg/kg, intraperitoneal injection daily over the 8-study day period). b A representative Oil red O staining of medulloblastoma sections from an untreated mouse (day 0) and a counterpart treated with GW9662 for 8 days. c Kaplan–Meyer survival curve of NeuroD2-SmoA1 medulloblastoma-bearing mice in days commenc- ing with initiation of treatment with DMSO or GW9662.; *P value \0.0001, Mantel–Cox test analysis). Magniﬁcation, 940. Bars 16 lM 597 assayed the effects of GW9662 treatment on survival of NeuroD2-SmoA1 medulloblastoma-bearing mice. As shown in Fig. 6c, from the time of tumor onset as deter- mined by appearance of detectable symptoms such as head tilt and altered gait and conﬁrmed by magnetic resonance imaging, the average length of survival of NeuroD2-SmoA1 animals treated with DMSO (N = 15) was approximately a week. In contrast, GW9662-treated mice (N = 6) lived for up to 16 days after tumor onset, a signiﬁcant increase in survival. These striking results suggest a therapeutic potential for PPARc inhibition in treating Shh-driven medulloblastomas. Discussion Cross talk between independent yet intertwined signaling pathways of metabolism and cancer is currently the topic of increasing scrutiny. We reported earlier a direct transcrip- tional link between the Rb/E2F tumor suppressor complex and PDK4 [17], a critical nutrient sensor and a regulator of mitochondrial glucose oxidation. In more recent work, we demonstrated that excessive mitogenic signaling by Shh, a driver of medulloblastoma, engages the Rb/E2F tumor suppressor complex, activates the key enzyme fatty acid synthase (FASN) and drives lipogenesis through a novel, E2F1-regulated process [2]. FASN has also been linked to survival in glioma cells with activating EGFR mutations [11, 12] and other tumors [25]. Many transformed cells also exhibit reliance on glutaminolysis [5, 43], a process associated with the activity of the myc oncogene [9, 46]. In addition, expression of key tumor suppressors such as p53, PTEN and LKB1 has been reported to inﬂuence important regulators of cellular metabolism [18]. Indeed, many signaling pathways implicated in routine surveillance themselves go awry across the spectrum of human diseases. Loss of metabolic inﬂexibility for instance is a pathological feature in disorders like diabetic cardiomyopathy as well as in certain cancers, where tumor cells’ addiction to de novo lipid synthesis for instance appears to be a deﬁning feature for proliferation and survival [2, 24]. In this study, we show that in medulloblastoma and CGNPs, the Shh pathway is coupled—through E2F1—to the steroid receptor PPARc and the control of glycolysis, a vital cellular process. This coupling underscores the broad inﬂuence of the hedgehog-regulated metabolic network. It is signiﬁcant given the role of PPARc as a modulator of cellular homeostasis as well as a therapeutic target in many chronic diseases [26]. Indeed, PPARc agonists are rou- tinely used for the treatment of patients with diabetes or hyperglycemia and it is established that activation of PPARc ameliorates insulin sensitivity in vivo and ex vivo. Nonetheless, the ﬁndings of this study reveal that 123