title: Hedgehog-mediated regulation of PPARγ controls metabolic patterns in neural precursors and shh-driven medulloblastoma.
abstract: Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum 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 progression, in an E2F1- and FASN-dependent manner. Here, we show that the nutrient sensor PPARγ is a key component of the Shh metabolic network, particularly its regulation of glycolysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposed medulloblastoma cells-of-origin, Shh stimulation elicits a marked induction of PPARγ alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPARγ expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPARγ and/or Rb inactivation inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcriptional 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 → PPARγ axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These findings emphasize the value of PPARγ downstream of Shh as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Bobby
authors.initials: B
authors.lastname: Bhatia
authors.forename: Chad R
authors.initials: CR
authors.lastname: Potts
authors.forename: Cemile
authors.initials: C
authors.lastname: Guldal
authors.forename: SunPhil
authors.initials: S
authors.lastname: Choi
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kenney
authors.forename: Zaher A
authors.initials: ZA
authors.lastname: Nahlé
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001391:Azo Compounds; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008527:Medulloblastoma / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism*; D049268:Positron-Emission Tomography; D013963:Thyroid Hormones / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000813:Anilides; D001391:Azo Compounds; D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors; D006593:Hexokinase; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D009479:Neuropeptides; D047495:PPAR gamma; D013963:Thyroid Hormones; D014157:Transcription Factors; D000097810:Thyroid Hormone-Binding Proteins; C457499:2-chloro-5-nitrobenzanilide; C493753:E2F1 protein, human; C528734:GLUT4 enhancer factor, mouse; C490925:NEUROD2 protein, human; C515658:HK1 protein, mouse; C011049:oil red O