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 3

EWS/ATF1-induced tumors arise from neural crest–lineage cells.

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EWS/ATF1-induced tumors arise from neural crest–lineage cells. (A) Im...
(A) Immunohistochemical analysis for CCS markers. Nuclear staining for S100, Sox10, and Mitf was observed in tumor cells. Sections were counterstained with hematoxylin. Scale bars: 100 μm. (B) Schematic representation of reporter alleles for the lineage-tracing experiment using Wnt1-Cre allele. Doxycycline-inducible EWS/ATF1 alleles were introduced into reporter mice containing the Wnt1-Cre and floxed LacZ reporter alleles. (C) X-gal staining for EWS/ATF1-induced tumors with Wnt1-Cre and floxed LacZ reporter alleles. Positive staining for X-gal indicated that the tumor arose from a neural crest–lineage cell. Histological analysis revealed that neoplastic cells were stained with X-gal. Counterstaining was performed with fast red. Scale bars: 2 mm (left); 50 μm (right). (D) Schematic representation of reporter alleles for the lineage-tracing experiment using P0-Cre allele. Doxycycline-inducible EWS/ATF1 alleles were introduced into reporter mice containing the P0-Cre and floxed EYFP reporter alleles. (E) Representative image of a tumor (arrow) in the trunk of an EWS/ATF1-induced mouse with P0-Cre and floxed EYFP reporter alleles. Fluorescent signals for EYFP expression were detected in the. Scale bars: 10 mm.