Acta Neuropathol (2012) 123:587–600 DOI 10.1007/s00401-012-0968-6 O R I G I N A L P A P E R Hedgehog-mediated regulation of PPARc controls metabolic patterns in neural precursors and shh-driven medulloblastoma Bobby Bhatia • Chad R. Potts • Cemile Guldal • SunPhil Choi • Andrey Korshunov • Stefan Pﬁster • Anna M. Kenney • Zaher A. Nahle´ Received: 10 October 2011 / Revised: 27 February 2012 / Accepted: 29 February 2012 / Published online: 11 March 2012 The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spec- trum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis. Indeed, such Shh-mediated metabolic reprogramming fuels tumor Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-0968-6) contains supplementary material, which is available to authorized users. B. Bhatia C. Guldal Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA C. R. Potts S. Choi A. M. Kenney Z. A. Nahle´ Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, USA A. M. Kenney Z. A. Nahle´ (&) Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA e-mail: zaher.nahle@vanderbilt.edu A. Korshunov Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany S. Pﬁster Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany Present Address: B. Bhatia Millipore Corporation, Billerica, MA, USA progression, in an E2F1- and FASN-dependent manner. Here, we show that the nutrient sensor PPARc is a key component of the Shh metabolic network, particularly its regulation of gly- colysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposed medulloblastoma cells- of-origin, Shh stimulation elicits a marked induction of PPARc alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPARc expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPARc and/or Rb inactivation inhibits CGNP proliferation, drives medullo- blastoma cell death and extends survival of medulloblastoma- bearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcrip- tional regulator deﬁne a novel mechanism through which Shh signaling engages the nutrient sensing machinery in brain cancer, controls the cell cycle, and regulates the glycolytic index. This also reveals a dominant role of Shh in the etiology of glucose metabolism in medulloblastoma and underscores the function of the Shh ? E2F1 ? PPARc axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These ﬁndings emphasize the value of PPARc downstream of Shh as a global therapeutic target in hedgehog- dependent and/or Rb-inactivated tumors. Keywords Medulloblastoma Cerebellum Metabolism PPARc Glycolysis Sonic hedgehog Cancer Tumor metabolism Introduction Medulloblastomas (MBs) remain the leading cause of death from solid cancers in children [30]. These predominantly 123