Abstract B20: Mouse models of Ewing's sarcoma and fusion-related sarcoma: Correct phenotypes and cell-of-origin

Abstract

Abstract Tumor-specific fusion genes associated with chromosomal translocations play an important role in development of bone and soft tissue sarcoma. Clarification of tumorigenic processes by fusion genes is valuable to understand disease mechanisms and to develop molecular targeted therapies. We have recently established ex vivo mouse models for Ewing's sarcoma (ES) by introducing EWS-FLI1 into mouse embryonic cells. The ES model enabled us to analyze tumorigenic processes from the initial step to the highly malignant stage, and to select important genetic pathways in the processes. The knockdown of the EWS-FLI1 target genes and members of the important signaling pathways significantly suppressed cell proliferation of ES in vitro. Importance of such pathways were further confirmed by using specific inhibitors for PARP, EZH2 or Wnt/β-catenin pathway both in vitro and in vivo. Moreover, Cre-loxp-mediated knockout of EWS-FLI1 showed that mouse ES growth is fusion gene-dependent. In addition, we have succeeded to generate synovial sarcoma, alveolar soft part sarcoma and Ewing-like sarcoma by introducing SYT-SSX1, ASPL-TFE3 or CIC-DUX4, respectively. These results indicate essential roles of fusion oncogenes in sarcomagenesis and tumor maintenance, and the epigenetic status of cell-of-origin. Our platform will allow us to explore and evaluate novel targeted therapies. Citation Format: Miwa Tanaka, Takuro Nakamura. Mouse models of Ewing's sarcoma and fusion-related sarcoma: Correct phenotypes and cell-of-origin. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B20.