一项“睡美人”正向遗传学筛选鉴定出驱动骨肉瘤发生和转移的新基因及信号通路。

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

作者信息

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

机构信息

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.

出版信息

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

DOI:10.1038/ng.3293

PMID:25961939

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4767150/

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.

摘要

骨肉瘤是一种骨的肉瘤，起源于成骨细胞或其前体细胞，具有较高的转移倾向。骨肉瘤与大量的基因组不稳定相关，这使得使用人类肿瘤或典型小鼠模型来鉴定驱动基因变得困难，其中许多模型涉及Trp53功能的丧失。为了鉴定驱动骨肉瘤发生和转移的基因，我们在有或没有Trp53体细胞缺失的小鼠中进行了基于Sleeping Beauty（SB）转座子的正向遗传筛选。对119个原发性肿瘤和134个转移结节的共同插入位点（CIS）分析分别鉴定出232个与骨肉瘤发生相关的位点和43个与转移相关的位点。对CIS相关基因的分析鉴定出许多已知的和新的骨肉瘤相关基因，这些基因在ErbB、PI3K-AKT-mTOR和MAPK信号通路中富集。最后，我们鉴定出了几个参与轴突导向的癌基因，包括Sema4d和Sema6d，我们在人类骨肉瘤中对其作为癌基因进行了功能验证。