Mouse models of Desmoplastic Small Round Cell Tumor and Ewings sarcoma

促结缔组织增生性小圆细胞肿瘤(DSRCT)是一种罕见但极具侵袭性的肿瘤，发生于腹部的青少年。在迄今检查的所有DSRCT病例中，涉及尤文斯肉瘤基因(EWS)和Wilms肿瘤抑制基因WT1的染色体易位导致这两个基因的融合，产生了一种新的转录因子。尤文肉瘤是一种不同类型的儿科肿瘤，其EWS基因与转录因子Ets家族的Fli-1基因融合。我们的兴趣集中在了解EWS/WT1和EWS/FLI1基因产物的分子功能以及它们如何在各自的癌症发生中起作用。为了实现这一目标，我们目前正在开发DSRCT和尤文氏肉瘤的小鼠模型，以更好地了解这些肿瘤的病因和在活体环境中的发展。目的1.利用基因打靶技术，建立染色体易位与DSRCT和尤文氏肉瘤相似的小鼠肿瘤模型。然后，成功靶向的小鼠ES细胞将被注射，以产生携带这些染色体易位的小鼠。目的2.我们将检查小鼠自发性肿瘤的形成，并通过与其他易患癌症的动物模型交叉引入二次突变，以期加速肿瘤的发生。Aim3.我们将从动物或形成的肿瘤中建立表达EWS/WT1和EWS/Fli-1易位的细胞系，并进行表达谱分析以及蛋白质组学(质谱学)以确定肿瘤形成途径和驱动转化的相互作用蛋白。我们的小鼠模型将有助于阐明这些儿童癌症的分子机制，所获得的知识也将有助于揭示具有类似特征的其他成人肿瘤。我们的模型对于开发针对DSRCT和尤因肉瘤的新疗法也将是无价的。

Desmoplastic small round cell tumor (DSRCT) is a rare but extremely aggressive cancer arising in young adolescents in the abdominal area. In all cases of DSRCT examined to date, a chromosomal translocation involving the Ewings Sarcoma gene (EWS) and the Wilms tumor suppressor gene, WT1, results in the fusion of the two genes, generating a novel transcription factor. In Ewing's sarcoma, which is a different type of pediatric tumor, EWS gene is fused to the Fli-1 gene, an ETS-family of transcription factor. Our interest is focused on understanding the molecular functions of EWS/WT1 and EWS/Fli1 gene products and how they contribute to tumorigenesis in their respective cancers. Towards this goal, we are currently developing mouse models of DSRCT and Ewing's sarcoma to better understand the etiology and the development of these tumors in the context of living organism. Aim 1. We will generate mouse models of these cancers with similar chromosomal tranlocations that are found in DSRCT and Ewing's sarcoma by using gene targeting approach. Successfully targeted mouse ES cells will then be injected to generate mice harboring these chromosomal translocations. Aim 2. We will examine the mice for the formation of spontaneous tumors and also to introduce secondary mutations by intercross with other cancer-prone animal models in hopes of accelerating tumorigenesis. Aim3. We will generate cell lines expressing the EWS/WT1 and EWS/Fli-1 translocations, either from the animals or from the tumors that are formed, and perform expression profiling analysis as well as proteomics (mass spectrometry) to identify tumorigenic pathways and interacting proteins that drive transformation. Our mouse models will help elucidate molecular mechanisms of these pediatric cancers and the knowledge gained will also shed light on the other adult tumors with similar characteristics. Our models will also be invaluable for the development of new therapeutics against DSRCT and Ewing'sarcoma.