Mouse models of Desmoplastic Small Round Cell Tumor and Ewings sarcoma

促结缔组织增生性小圆细胞瘤和尤文氏肉瘤的小鼠模型

• 批准号: 8349844
• 负责人: Sean Lee
• 金额: $ 45.06万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349844
• 关键词: Abdomen; Adolescent; Adult; Animal Model; Animals; Area; Cell Line; Characteristics; Chromosomal translocation; Desmoplastic Small Round Cell Tumor; Development; Disease; ETS Family Gene; Etiology; Ewings sarcoma; Gene Targeting; Genes; Goals; Human; In Vitro; Knowledge; Lead; Life; Light; Malignant Childhood Neoplasm; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Organism; Pathway interactions; Pediatric Neoplasm; Proteins; Proteomics; Reagent; Testing; Tumor Suppressor Genes; WT1 gene; Wilms Tumor Genes; conventional therapy; embryonic stem cell; in vivo; interest; mouse model; novel; novel therapeutics; tool; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

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.

促纤维增生性小圆细胞瘤 (DSRCT) 是一种罕见但极具侵袭性的癌症，发生于青少年腹部。在迄今为止检查的所有 DSRCT 病例中，涉及尤文肉瘤基因 (EWS) 和维尔姆斯肿瘤抑制基因 WT1 的染色体易位导致这两个基因融合，产生一种新的转录因子。在尤文氏肉瘤（一种不同类型的儿科肿瘤）中，EWS 基因与转录因子 ETS 家族 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有机体背景下的病因和发展。目标 1. 我们将利用基因打靶方法，建立这些具有与 DSRCT 和尤文氏肉瘤中发现的相似染色体易位的癌症的小鼠模型。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杂交来引入二次突变，以期加速肿瘤的发生。目标3。我们将从动物或形成的肿瘤中生成表达 EWS/WT1 和 EWS/Fli-1 易位的细胞系，并进行表达谱分析和蛋白质组学（质谱），以确定致瘤途径和驱动转化的相互作用蛋白质。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了解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 和尤文肉瘤的新疗法也将具有无价的价值。