title: 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.affiliation: Department of Orthopedic Surgery, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamada
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Ohno
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aoki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Semi
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritake
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shiozawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
authors.forename: Katsuji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D015870:Gene Expression; D050939:Gene Fusion; D016762:Genes, fos; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D018227:Sarcoma, Clear Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; C111598:EWS-ATF1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors