A novel oncogenic driver in Ewing sarcoma

尤文肉瘤的一种新的致癌驱动因素

基本信息

批准号：
9179478
负责人：
YUZURU SHIIO
金额：
$ 19.9万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-27 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9179478
关键词：
Accounting Address Binding Biological Bone Tissue Cell Line Cells Characteristics Child Chromosomal translocation Chromosomes Clinical Cloning Data Development Disease EWS-FLI1 fusion protein Ewings sarcoma Failure Family Future Gene Expression Genetic Growth Human Investigation Light Malignant Neoplasms Mesenchymal Stem Cells Modeling Mus Mutation Northern Blotting Oncogenes Oncogenic Other Genetics Outcome Pathogenesis Phase Phenotype Play Protein Isoforms Public Health RNA Splicing Recurrence Research Role Sampling Staging TP53 gene Testing Toxic effect Transgenic Mice Tumor Angiogenesis Tumor Cell Line Tumorigenicity Vascular Endothelial Growth Factors cell type disease phenotype fusion gene genome sequencing knock-down mouse model novel novel therapeutic intervention protein protein interaction soft tissue targeted treatment transcription factor

项目摘要

This exploratory project is directed towards understanding the biological role of a novel oncogenic driver in Ewing sarcoma. Ewing sarcoma is an aggressive cancer of bone and soft tissues in children with poor long- term outcome. It is characterized by the chromosomal translocation generating a fusion oncogene between EWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 translocation accounts for 85% of Ewing sarcoma cases. Since the cloning of the EWS-FLI-1 fusion oncogene, the predominant view in the Ewing sarcoma field has been that EWS-FLI-1 plays a central role in Ewing sarcomagenesis. EWS-FLI-1 is able to transform mouse cells such as NIH3T3 and C3H10T1/2 and the knockdown of EWS-FLI-1 inhibits the survival, proliferation and tumorigenicity of Ewing sarcoma cells, suggesting that EWS-FLI-1 is the causative oncogene. However, a variety of evidence also suggest that EWS-FLI-1 alone cannot fully explain the Ewing sarcomagenesis: 1) EWS-FLI-1 alone cannot transform any human cell types including human mesenchymal stem cells which are the putative cells of origin of Ewing sarcoma; 2) Generating a transgenic mouse model of Ewing sarcoma by using EWS-FLI-1 alone has been unsuccessful; and 3) Other genetic alterations such as mutations of INK4a and p53 confer worse clinical outcome. The applicant's group has identified a novel oncogenic driver for Ewing sarcoma, which is required for Ewing sarcoma proliferation and which cooperates with EWS-FLI-1 in mesenchymal stem cells. This project will address the biological role of this novel oncogenic driver in Ewing sarcoma by pursuing the following two specific aims: 1) Delineate its role in established Ewing sarcoma and 2) Modelling Ewing sarcoma by co- expression with EWS-FLI-1. The proposed research has the potential to shed new light on the long-standing conundrums in the Ewing sarcoma field such as the inability of EWS-FLI-1 to transform any human cell types, the failure to develop a genetic mouse model of Ewing sarcoma using EWS-FLI-1 alone, and the lack of a targeted therapy for Ewing sarcoma.

该探索性项目旨在了解新型致癌驱动因素的生物学作用尤因肉瘤。尤文肉瘤是一种侵袭性骨和软组织癌症，发生于患有长期营养不良的儿童。期限结果。其特征是染色体易位产生融合癌基因 EWS 和 Ets 家族转录因子，最常见的是 FLI-1。 EWS-FLI-1易位占85% 尤文肉瘤病例。自从EWS-FLI-1融合癌基因克隆以来，尤文肉瘤领域的主流观点 EWS-FLI-1 在尤文肉瘤发生中起着核心作用。 EWS-FLI-1能够转变 NIH3T3 和 C3H10T1/2 等小鼠细胞以及 EWS-FLI-1 的敲低会抑制其存活，尤文肉瘤细胞的增殖和致瘤性，表明 EWS-FLI-1 是致病基因。然而，各种证据也表明EWS-FLI-1本身并不能完全解释尤因肉瘤发生：1）EWS-FLI-1单独不能转化任何人类细胞类型，包括人类间充质细胞干细胞是尤文肉瘤的假定起源细胞； 2) 构建转基因小鼠模型单独使用 EWS-FLI-1 治疗尤文肉瘤尚未成功； 3) 其他基因改变，例如 INK4a 和 p53 突变会导致更差的临床结果。申请人的小组已经确定了尤文肉瘤的一种新型致癌驱动因素，这是尤文肉瘤的增殖与间充质干细胞中的EWS-FLI-1协同作用。本项目将通过以下两个研究来解决尤文肉瘤中这种新型致癌驱动因素的生物学作用具体目标：1）描述其在已建立的尤文肉瘤中的作用，2）通过共同对尤文肉瘤进行建模用 EWS-FLI-1 表达。拟议的研究有可能为解决该领域长期存在的难题提供新的线索。尤文肉瘤领域，例如 EWS-FLI-1 无法转化任何人类细胞类型，无法单独使用 EWS-FLI-1 开发尤文肉瘤遗传小鼠模型，且缺乏靶向治疗用于尤文肉瘤。