EWS/ATF1 expression induces sarcomas from neural crest–derived cells in mice
Copyright policy )EWS/ATF1 expression induces sarcomas from neural crest–derived cells in mice
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.
- Kyushu University Japan
- Kyoto University Japan
- University of Miyazaki Japan
- Gifu University Japan
- Tokai National Higher Education and Research System Japan
Activating Transcription Factor 1, Base Sequence, Oncogene Proteins, Fusion, Gene Expression, Genes, fos, Mice, Transgenic, Mice, Neural Crest, Cell Line, Tumor, Animals, Humans, Cell Lineage, Sarcoma, Clear Cell, Gene Fusion, RNA, Small Interfering, RNA-Binding Protein EWS, Cell Proliferation, Transcription Factors
Activating Transcription Factor 1, Base Sequence, Oncogene Proteins, Fusion, Gene Expression, Genes, fos, Mice, Transgenic, Mice, Neural Crest, Cell Line, Tumor, Animals, Humans, Cell Lineage, Sarcoma, Clear Cell, Gene Fusion, RNA, Small Interfering, RNA-Binding Protein EWS, Cell Proliferation, Transcription Factors
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