title: The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.
abstract: Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.
authors.affiliation: 1] Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China. [2] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Xuelian
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Xiamen University, Fujian, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.affiliation: Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Fanghui
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Hu
authors.affiliation: Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Se Hoon
authors.identifier: 0000000175167372
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.affiliation: Department of Neurology, Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
authors.affiliation: Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wechsler-Reya
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: 1] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China. [3] Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs