Modeling Clear Cell Sarcomagenesis in the Mouse: Cell of Origin Differentiation State Impacts Tumor Characteristics

SummaryClear cell sarcoma (CCS) of tendons and aponeuroses is a deadly soft-tissue malignancy resembling melanoma, with a predilection for young adults. EWS-ATF1, the fusion product of a balanced chromosomal translocation between chromosomes 22 and 12, is considered the definitional feature of the tumor. Conditional expression of the EWS-ATF1 human cDNA in the mouse generates CCS-like tumors with 100% penetrance. Tumors, developed through varied means of initiating expression of the fusion oncogene, model human CCS morphologically, immunohistochemically, and by genome-wide expression profiling. We also demonstrate that although fusion oncogene expression in later stages of differentiation can transform mesenchymal progenitor cells and generate tumors resembling CCS generally, expression in cells retaining stem cell markers permits the full melanoma-related phenotype.

► Clear cell sarcoma fusion gene EWS-ATF1 expression produces tumors in 100% of mice ► EWS-ATF1-driven mouse tumors model human tumors histology and gene expression profile ► A range of mouse cells tolerates EWS-ATF1 expression and subsequently yields tumors ► The differentiation state of the transforming cells impacts tumor characteristics