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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2013-02, Vol.123 (2), p.600-610
Main Authors: Yamada, Kazunari, Ohno, Takatoshi, Aoki, Hitomi, Semi, Katsunori, Watanabe, Akira, Moritake, Hiroshi, Shiozawa, Shunichi, Kunisada, Takahiro, Kobayashi, Yukiko, Toguchida, Junya, Shimizu, Katsuji, Hara, Akira, Yamada, Yasuhiro
Format: Article
Language:English
Subjects:
Activating Transcription Factor 1 - genetics
Animals
Base Sequence
Biomedical research
Care and treatment
Cell Line, Tumor
Cell Lineage - genetics
Cell Proliferation
Development and progression
Gene Expression
Gene Fusion
Genes
Genes, fos
Genetic aspects
Health aspects
Humans
Kinases
Melanoma
Mice
Mice, Transgenic
Neural Crest - pathology
Oncogene Proteins, Fusion - genetics
Physiological aspects
Proteins
RNA polymerase
RNA, Small Interfering - genetics
RNA-Binding Protein EWS - genetics
Sarcoma
Sarcoma, Clear Cell - etiology
Sarcoma, Clear Cell - genetics
Sarcoma, Clear Cell - pathology
Skin cancer
Transcription factors
Transcription Factors - genetics
Transgenic animals
Tumors
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Description
Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI63572