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      EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice.

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          Abstract

          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.

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          Author and article information

          Journal
          J. Clin. Invest.
          The Journal of clinical investigation
          American Society for Clinical Investigation
          1558-8238
          0021-9738
          Feb 2013
          : 123
          : 2
          Affiliations
          [1 ] Department of Orthopedic Surgery, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
          Article
          63572
          10.1172/JCI63572
          3561811
          23281395

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