title: A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.
abstract: Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.
authors.affiliation: 1] Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA. [2] Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA. [3] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Branden S
authors.initials: BS
authors.lastname: Moriarity
authors.affiliation: 1] Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA. [2] Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA. [3] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [4] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Otto
authors.affiliation: 1] Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA. [2] Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA. [3] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [4] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Rahrmann
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Rathe
authors.affiliation: 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Wolf
authors.affiliation: 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Madison T
authors.initials: MT
authors.lastname: Weg
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Manlove
authors.affiliation: 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: LaRue
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Nuri A
authors.identifier: 0000000314163639
authors.initials: NA
authors.lastname: Temiz
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Holly
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota, USA.
authors.forename: Milcah C
authors.initials: MC
authors.lastname: Scott
authors.affiliation: BioNet, Academic Health Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Forster
authors.affiliation: 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota, USA. [3] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.affiliation: Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.affiliation: Tissue Array Research Program (TARP), Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.affiliation: Department of Orthopedic Surgery, Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1] Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA. [2] Department of Molecular Pharmacology, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
authors.affiliation: 1] Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA. [2] Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA. [3] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [4] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D004251:DNA Transposable Elements; D004285:Dogs; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D012516:Osteosarcoma / Q000235:genetics* / Q000556:secondary; D051059:PTEN Phosphohydrolase / Q000235:genetics; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; C103150:Sema4d protein, mouse; C483479:Sema6d protein, mouse; D039961:Semaphorins; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse