期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11745-1
关键词
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资金
- AMED-CREST [JP18gm1110004]
- AMED P -CREATE [JP18cm0106203]
- JSPS KAKENHI [18H04026]
- Research Grants of Princess Takamatsu Cancer Research Fund
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Naito Foundation
- World Premier International Research Center Initiative (WPI), MEXT, Japan
- Grants-in-Aid for Scientific Research [18H04026] Funding Source: KAKEN
Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development.
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