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EWS/ATF1 activates Fos and induces soft tissue sarcomas [Affymetrix].

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE41121 | GEO | 2013/04/04

SECONDARY ACCESSION(S): PRJNA176040

REPOSITORIES: GEO

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

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 established from soft tissue sarcomas in EWS/ATF1-induced mice. Because these cell lines contain doxycycline-inducible EWS/ATF1 alleles, EWS/ATF1 expression can be regulated by the different concentrations of doxycycline. Tumor cell lines were exposed to different concentrations of doxycycline, and total RNAs were isolated at 3 and 48 hours after the doxycycline exposure.

2013-04-04 | E-GEOD-41122 | biostudies-arrayexpress

EWS/ATF1 activates Fos and induces soft tissue sarcomas [Affymetrix].

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

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

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Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

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.

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

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

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The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets

Project description:The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here, we dissect the profiles of the reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal the molecular mechanisms underlying this phenomenon. Using clear cell sarcomas (CCSs) as a model, we show that expression of the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancer elements and thereby impairs the early transcriptional response toward pluripotency which is otherwise provoked. Consistently, sensitization to the reprogramming cue is also observed in other types of cancer when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional ‘stiffness’, we identify the mTOR signaling pathway downstream of EWS/ATF1, and discover inhibiting the mTOR activity substantially attenuates the propagation of CCS cells both in vitro and in vivo. Collectively, our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics in cancer cells. Moreover, the current study has implications for understanding how the cancer cell identity is robustly maintained.

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Project description:The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here, we dissect the profiles of the reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal the molecular mechanisms underlying this phenomenon. Using clear cell sarcomas (CCSs) as a model, we show that expression of the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancer elements and thereby impairs the early transcriptional response toward pluripotency which is otherwise provoked. Consistently, sensitization to the reprogramming cue is also observed in other types of cancer when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional ?stiffness?, we identify the mTOR signaling pathway downstream of EWS/ATF1, and discover inhibiting the mTOR activity substantially attenuates the propagation of CCS cells both in vitro and in vivo. Collectively, our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics in cancer cells. Moreover, the current study has implications for understanding how the cancer cell identity is robustly maintained.

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Mus musculus

Project description:EWS/ATF1 activates Fos and induces soft tissue sarcomas [Affymetrix].

| PRJNA176040 | ENA