EWS/ATF1 activates Fos and induces soft tissue sarcomas from neural crest-derived cells

2014 Fiscal Year Final Research Report

• Project/Area Number: 24592229
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Gifu University
• Principal Investigator: OHNO Takatoshi 岐阜大学, 医学(系)研究科(研究院), 准教授 (60281052)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 明細胞肉腫 / 融合遺伝子 / EWS-ATF1 / Fos / 分子標的治療 / トランスジェニックマウス / 軟部肉腫

Outline of Final Research Achievements

Clear cell sarcoma (CCS) is characterized by t(12; 22) translocation, leading to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying how EWS/ATF1 is involved in the development of CCSs. We generated EWS/ATF1-inducible mice, and examined the effects of EWS/ATF1 expression in adult cells. We show that the forced expression of EWS/ATF1 results in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembles that of CCSs and EWS/ATF1-induced tumor cells express CCS-markers, such as Mitf. A lineage tracing experiment revealed that such sarcomas are derived from neural crest-lineage cells. Finally, we found that EWS/ATF1 directly induces Fos in an ERK-independent manner, and demonstrated that the increased Fos expression is important for the active cell proliferations. Our results indicate that FOS could be a promising therapeutic target for the treatment of EWS/ATF1-related sarcomas.

Free Research Field

骨軟部腫瘍