title: The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.
abstract: During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mille
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, 845 Sherbrooke Street West, Montréal QC H3A 0G4, Canada.
authors.forename: Lukas
authors.initials: L
authors.lastname: Tamayo-Orrego
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Lévesque
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto ON M5G 1L7, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Cardin
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouchard
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada.
authors.forename: Luisa
authors.initials: L
authors.lastname: Izzi
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto ON M5G 1L7, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada; Integrated Program in Neuroscience, McGill University, 845 Sherbrooke Street West, Montréal QC H3A 0G4, Canada; Department of Anatomy and Cell Biology, Department of Biology, and Division of Experimental Medicine, McGill University, 845 Sherbrooke Street West, Montréal QC H3A 0G4, Canada. Electronic address: frederic.charron@ircm.qc.ca.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004249:DNA Damage; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C510745:Boc protein, mouse; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D019938:Cyclin D1