A novel oncogenic driver in Ewing sarcoma

尤文肉瘤的一种新的致癌驱动因素

• 批准号: 9321922
• 负责人: YUZURU SHIIO
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-27 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321922
• 关键词: Address; Binding; Biological; Bone Tissue; Capers; 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; Impairment; Investigation; Light; Malignant Bone Neoplasm; 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; TP53 gene; Testing; Toxic effect; Transgenic Mice; Tumor Angiogenesis; 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; tumor

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.

该探索性项目旨在理解新型致癌驱动器在 尤因肉瘤。尤因肉瘤是长期不良儿童的骨骼和软组织的侵略性癌 术语结果。它的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EWS-FLI-1融合癌基因的克隆以来，Ewing肉瘤领域的主要视图 EWS-FLI-1在Ewing肉瘤中起着核心作用。 EWS-FLI-1能够转换 小鼠细胞（例如NIH3T3和C3H10T1/2）以及EWS-FLI-1的敲低抑制了生存， ewing肉瘤细胞的增殖和肿瘤性，表明EWS-FLI-1是致病性癌基因。 但是，各种证据也表明，仅EWS-FLI-1无法完全解释Ewing 肉瘤作用：1）仅EWS-FLI-1不能转化任何人类细胞类型，包括人类质质 干细胞是尤因肉瘤起源的推定细胞； 2）生成的转基因小鼠模型 仅使用EWS-FLI-1的EWING肉瘤并没有成功； 3）其他遗传改变，例如 Ink4a和p53的突变赋予较差的临床结果。 申请人的小组已经确定了尤因肉瘤的新型致癌驱动器，这是必需的 Ewing肉瘤增殖，并与EWS-FLI-1合作在间充质干细胞中。这个项目 通过追求以下两个 具体目的：1）描述其在已建立的尤因肉瘤中的作用，以及2）通过共同建模Ewing肉瘤 用EWS-FLI-1表达。 拟议的研究有可能对长期存在的难题进行新的启示 EWING肉瘤领域，例如EWS-FLI-1无法转化任何人类细胞类型的能力 仅使用EWS-FLI-1开发ewing肉瘤的遗传小鼠模型，并且缺乏靶向疗法 对于尤因肉瘤。