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.
The proposed research is relevant to public health because characterization of a novel oncogenic driver in Ewing sarcoma will increase the understanding of the pathogenesis of this disease and may shift the research paradigm in the field, potentially leading to novel therapeutic approaches.
|Jayabal, Panneerselvam; Houghton, Peter J; Shiio, Yuzuru (2017) EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1. Genes Cancer 8:762-770|