Similar Datasets
Project description: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.
| S-EPMC6728361 | biostudies-literature
Project description: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.
2019-07-18 | GSE77204 | GEO
Project description: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.
2019-07-18 | GSE77203 | GEO
Project description: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.
2019-08-01 | GSE124873 | GEO
Project description:Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
| PRJNA309695 | ENA
Project description:Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
| PRJNA514052 | ENA
Project description:Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
| PRJNA311226 | ENA
Project description: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.
| S-EPMC3561811 | biostudies-literature
Project description:Clear cell odontogenic carcinoma (CCOC) is a rare, low-grade malignant epithelial neoplasm, occurring in the jawbones, mainly affecting the mandible of elderly patients. In addition to hyalinizing clear cell carcinoma of the salivary gland, it is one of the epithelial neoplasms known to harbor an EWSR1-ATF1 fusion. Therefore, a link between these tumors seems plausible. We describe six cases of CCOC showing EWSR1 rearrangements, with two cases being positive for the ATF1 partner gene using FISH analysis. In one case, an EWSR1-CREB1 fusion was identified using RT-PCR, which we report for the first time in this tumor type. The other three cases investigated by FISH were negative for ATF1, CREB1 and CREB3L2. In conclusion, our data show that EWSR1-CREB1 is an alternative fusion gene to EWSR1-ATF1 in CCOC.
| S-EPMC6514205 | biostudies-literature
Project description:Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique 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. In addition, the cells of origin for CCSs remain to be determined. 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 S100, Sox10, and 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 proliferation in not only EWS/ATF1-induced sarcomas, but also in human CCSs. Our results indicate that FOS, as well as EWS/ATF1 itself, could be a promising therapeutic target for the treatment of EWS/ATF1-related sarcomas. Tumor cell lines were exposed to different concentrations of doxycycline, and total RNAs were isolated at 24 hours after the doxycycline exposure. Total RNAs were also isolated directly from a tumor developed in a EWS/ATF1-inducible mouse given doxycycline for 3 months. The doxycycline concentration and time point for each sample is EWS-ATF1_control; 0 microg/ml (no dox), 24 hours after the exposure, EWS-ATF1_24h_highDox; 0.2 microg/ml, 24 hours after the exposure and EWS-ATF1_tumor1; a tumor was resected from a EWS/ATF1-inducible mouse given doxycycline for 3 months.
2013-04-04 | E-GEOD-41121 | biostudies-arrayexpress