A novel oncogenic driver in Ewing sarcoma

这个探索性的项目旨在了解一种新的致癌驱动因子在肿瘤发生中的生物学作用。 尤因肉瘤。尤文肉瘤是一种侵袭性的骨和软组织癌症，发生在生长不良的儿童身上， 长期成果。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% 尤因肉瘤病例。 自从EWS-FLI-1融合癌基因被克隆以来，尤文肉瘤领域的主流观点 EWS-FLI-1在尤文肉瘤发生中起着重要作用。EWS-FLI-1能够将 小鼠细胞如NIH 3 T3和C3 H10 T1/2和EWS-FLI-1的敲低抑制了存活， EWS-FLI-1是尤文肉瘤细胞的致癌基因。 然而，各种证据也表明，EWS-FLI-1本身不能完全解释Ewing 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，其是尤文肉瘤的假定起源细胞; 2）产生尤文肉瘤的转基因小鼠模型， 通过单独使用EWS-FLI-1的尤文肉瘤是不成功的;和3）其他遗传改变，如 INK 4a和p53的突变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的致癌驱动因子，这是尤文肉瘤发生所必需的。 EWS-FLI-1在间充质干细胞中的协同作用。这个项目 我将通过以下两个方面来阐述这种新型致癌驱动因子在尤文肉瘤中的生物学作用 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 EWS-FLI-1的表达。 这项拟议中的研究有可能为人类历史上长期存在的难题提供新的线索。 EWS-FLI-1不能转化任何人类细胞类型， 单独使用EWS-FLI-1开发尤文肉瘤的遗传小鼠模型，缺乏靶向治疗 尤因肉瘤

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.