EWS/ATF1 expression induces sarcomas from neural crest–derived cells in mice
Kazunari Yamada, … , Akira Hara, Yasuhiro Yamada
Kazunari Yamada, … , Akira Hara, Yasuhiro Yamada
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):600-610. https://doi.org/10.1172/JCI63572.
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Research Article Oncology

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

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.

Authors

Kazunari Yamada, Takatoshi Ohno, Hitomi Aoki, Katsunori Semi, Akira Watanabe, Hiroshi Moritake, Shunichi Shiozawa, Takahiro Kunisada, Yukiko Kobayashi, Junya Toguchida, Katsuji Shimizu, Akira Hara, Yasuhiro Yamada

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Figure 2

EWS/ATF1-induced tumors resemble human CCS.

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EWS/ATF1-induced tumors resemble human CCS. EWS/ATF1 transgenic mice ...
EWS/ATF1 transgenic mice were administered 50 μg/ml doxycycline in their drinking water for 3 months. (A) EWS/ATF1 expression caused tumor formation (arrows) in various locations: trunk, head, limbs, and whisker pads. X-ray examination revealed multiple tumors in deep soft tissue. The cut surface of a large tumor on the ventral trunk of an EWS/ATF1-inducible mouse revealed a lobulated gray-white mass in the deep soft tissue. Scale bars: 20 mm. (B) Histological analysis of EWS/ATF1-induced tumors. Tumors were composed of round or fusiform cells with prominent basophilic nuclei and clear cytoplasm, which were surrounded by fibrous fascicles. HA immunostaining confirmed EWS/ATF1 expression in the tumor cells. Frequent Ki67-positive cells were present throughout the lesions. Scale bars: 200 μm (H&E, left); 50 μm (H&E, right); 100 μm (HA and Ki67).