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

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

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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 language	English (US)
Pages (from-to)	615-624
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3293
State	Published - May 27 2015

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© 2015 Nature America, Inc. All rights reserved.

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Moriarity, B. S., Otto, G. M., Rahrmann, E. P., Rathe, S. K., Wolf, N. K., Weg, M. T., Manlove, L. A., Larue, R. S., Temiz, N. A., Molyneux, S. D., Choi, K., Holly, K. J., Sarver, A. L., Scott, M. C., Forster, C. L., Modiano, J. F., Khanna, C., Hewitt, S. M., Khokha, R., ... Largaespada, D. A. (2015). A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nature Genetics, 47(6), 615-624. https://doi.org/10.1038/ng.3293

Moriarity, BS, Otto, GM, Rahrmann, EP, Rathe, SK, Wolf, NK, Weg, MT, Manlove, LA, Larue, RS , Temiz, NA, Molyneux, SD, Choi, K, Holly, KJ, Sarver, AL, Scott, MC, Forster, CL, Modiano, JF, Khanna, C, Hewitt, SM, Khokha, R, Yang, Y, Gorlick, R, Dyer, MA & Largaespada, DA 2015, 'A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis', Nature Genetics, vol. 47, no. 6, pp. 615-624. https://doi.org/10.1038/ng.3293

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

Abstract

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