A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

Branden S Moriarity; George M Otto; Eric P Rahrmann; Susan K Rathe; Natalie K Wolf; Madison T Weg; Luke A Manlove; Rebecca S LaRue; Nuri A Temiz; Sam D Molyneux; Kwangmin Choi; Kevin J Holly; Aaron L Sarver; Milcah C Scott; Colleen L Forster; Jaime F Modiano; Chand Khanna; Stephen M Hewitt; Rama Khokha; Yi Yang; Richard Gorlick; Michael A Dyer; David A Largaespada

doi:10.1038/ng.3293

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

Nat Genet. 2015 Jun;47(6):615-24. doi: 10.1038/ng.3293. Epub 2015 May 11.

Authors

Branden S Moriarity¹, George M Otto², Eric P Rahrmann², Susan K Rathe³, Natalie K Wolf⁴, Madison T Weg⁴, Luke A Manlove⁵, Rebecca S LaRue⁶, Nuri A Temiz³, Sam D Molyneux⁷, Kwangmin Choi⁸, Kevin J Holly⁵, Aaron L Sarver³, Milcah C Scott⁹, Colleen L Forster¹⁰, Jaime F Modiano¹¹, Chand Khanna¹², Stephen M Hewitt¹³, Rama Khokha⁷, Yi Yang¹⁴, Richard Gorlick¹⁵, Michael A Dyer¹⁶, David A Largaespada²

Affiliations

¹ 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.
² 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.
³ Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
⁴ 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
⁵ Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
⁶ 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
⁷ Ontario Cancer Institute, Toronto, Ontario, Canada.
⁸ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁹ 1] Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. [2] Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota, USA.
¹⁰ BioNet, Academic Health Center, University of Minnesota, Minneapolis, Minnesota, USA.
¹¹ 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.
¹² Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
¹³ Tissue Array Research Program (TARP), Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
¹⁴ Department of Orthopedic Surgery, Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing, China.
¹⁵ 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.
¹⁶ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

PMID: 25961939
PMCID: PMC4767150
DOI: 10.1038/ng.3293

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Neoplasms / genetics*
Bone Neoplasms / pathology
Carcinogenesis / genetics
Cell Line, Tumor
DNA Transposable Elements
Dogs
Genetic Predisposition to Disease
Genomic Instability
Humans
Mice, Transgenic
Mutagenesis, Insertional
Osteosarcoma / genetics*
Osteosarcoma / secondary
PTEN Phosphohydrolase / genetics
Semaphorins / genetics
Semaphorins / metabolism
Tumor Suppressor Protein p53 / genetics

Substances

DNA Transposable Elements
Sema4d protein, mouse
Sema6d protein, mouse
Semaphorins
Tumor Suppressor Protein p53
PTEN Phosphohydrolase
Pten protein, mouse

Abstract

Publication types

MeSH terms

Substances

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