Mouse models of Desmoplastic Small Round Cell Tumor and Ewings sarcoma

结缔组织增生小圆细胞瘤（DSRCT）是一种罕见但极具侵袭性的肿瘤，多发于青少年腹部。在迄今为止检查的所有DSRCT病例中，涉及尤因斯肉瘤基因（EWS）和Wilms肿瘤抑制基因WT1的染色体易位导致两个基因融合，产生一种新的转录因子。Ewing肉瘤是一种不同类型的儿童肿瘤，EWS基因与ets转录因子家族中的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促进各自癌症的肿瘤发生。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在活体环境下的病因和发展。目的1。我们将使用基因靶向方法生成这些癌症的小鼠模型，这些癌症具有在DSRCT和尤文氏肉瘤中发现的类似染色体易位。然后将成功靶向的小鼠胚胎干细胞注射到具有这些染色体易位的小鼠体内。目标2。我们将检查小鼠自发肿瘤的形成，并通过与其他易患癌症的动物模型交叉引入继发性突变，以期加速肿瘤的发生。Aim3。我们将从动物或已形成的肿瘤中产生表达EWS/WT1和EWS/ fl -1易位的细胞系，并进行表达谱分析和蛋白质组学（质谱）分析，以确定致瘤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，所获得的知识也将揭示具有类似特征的其他成人肿瘤。我们的模型对于DSRCT和尤文氏肉瘤的新疗法的开发也将是无价的。

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.