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 YangRichard Gorlick, Michael A. Dyer, David A. Largaespada

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalNature Genetics
Volume47
Issue number6
DOIs
StatePublished - May 27 2015

Bibliographical note

Funding Information:
B.S.M. was funded by US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Musculoskeletal Training Grant AR050938. This research was funded by the Sobiech Osteosarcoma Fund Award, the Children’s Cancer Research Fund, an American Cancer Center Research Professor Grant (123939) and National Cancer Institute grant R01 CA113636 (to D.A.L.). We extend our thanks to the University of Minnesota resources involved in our project. The University of Minnesota Genomics Center provided services for RNA sequencing, oligonucleotide preparation and Sanger sequencing. The Minnesota Supercomputing Institute maintains the Galaxy software platform, as well as provides data management services and training. The cytogenetic analyses were performed in the Cytogenomics Shared Resource at the University of Minnesota with support from the comprehensive Masonic Cancer Center (US National Institutes of Health grant P30 CA077598).

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

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