A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.
A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.
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DOI：
10.1038/ng.3293
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发表时间：
2015-06
期刊：
影响因子：
30.8
通讯作者：
Largaespada DA
中科院分区：
文献类型：
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作者：
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
骨肉瘤是骨肉瘤，来源于成骨细胞或其前体细胞，具有高转移倾向。骨肉瘤与大量的基因组不稳定性相关，使得使用人类肿瘤或原型小鼠模型识别驱动基因成为问题，其中许多涉及Trp 53功能的丧失。为了鉴定驱动骨肉瘤发展和转移的基因，我们在有和没有Trp 53体细胞丢失的小鼠中进行了基于睡美人（SB）转座子的正向遗传筛选。对119例原发性肿瘤和134例转移性结节的共同插入部位（CIS）分析分别确定了232个与骨肉瘤发展相关的部位和43个与转移相关的部位。CIS相关基因的分析鉴定了许多已知的和新的骨肉瘤相关基因，这些基因在ErbB、PI 3 K-AKT-mTOR和MAPK信号通路中富集。最后，我们确定了几个参与轴突导向的癌基因，包括Sema 4d和Sema 6d，我们在功能上验证了它们是人骨肉瘤中的癌基因。
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.