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The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE168815 | GEO | 2023/02/19

REPOSITORIES: GEO

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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.

2023-02-19 | GSE189931 | GEO

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

2013-04-04 | GSE41122 | GEO

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

2013-04-04 | GSE41121 | GEO

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

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.

2019-08-01 | GSE124873 | GEO

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

2019-07-18 | GSE77204 | GEO

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

2019-07-18 | GSE77203 | GEO

Clear cell sarcoma human HEEBO microarray data

Project description:Clear cell sarcoma (CCS) of tendons and aponeuroses is a deadly soft-tissue malignancy resembling melanoma, with a predilection for young adults. EWS-ATF1, the fusion product of a balanced chromosomal translocation between chromosomes 22 and 12, is considered the definitional feature of the tumor. Conditional expression of the EWS-ATF1 human cDNA in the mouse generates CCS-like tumors with 100 percent penetrance. Tumors, developed through varied means of initiating expression of the fusion oncogene, model human CCS morphologically, immunohistochemically, and by genome-wide expression profiling. We also demonstrate that while fusion oncogene expression in later stages of differentiation can transform mesenchymal progenitor cells and generate tumors resembling CCS generally, expression in cells retaining stem cell markers permits the full melanoma-related phenotype. Nielsen et al. ("Molecular characterisation of soft tissue tumours: a gene expression study"; PMID 11965276) used microarray to compare a variety of soft-tissue neoplasms morphologically similar to clear cell sarcoma. In our study, we use their expression data (not previously submitted) in the profiling of our mouse mutant that models clear cell sarcoma.

2012-12-20 | GSE43045 | GEO

USP1 expression driven by EWS-FLI1 transcription factor stabilizes Survivin and promotes Ewing sarcoma cell survival

Project description:Ewing sarcoma (EWS) is a malignant pediatric bone cancer. Most Ewing sarcomas are driven by EWS-FLI1 oncogenic transcription factor that plays roles in transcriptional regulation, DNA damage response, cell cycle checkpoint control, and alternative splicing. USP1, a deubiquitylase which regulates DNA damage and replication stress responses, is overexpressed at both the mRNA and protein levels in EWS cell lines compared to human mesenchymal stem cells, the EWS cell of origin. The functional significance of high USP1 expression in Ewing sarcoma is not known. Here, we identify USP1 as a transcriptional target of EWS-FLI1 and a key regulator of EWS cell survival. We show that EWS-FLI1 knockdown decreases USP1 mRNA and protein levels. ChIP and ChIP-seq analyses show EWS-FLI1 occupancy on the USP1 promoter. Importantly, USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. We observe destabilization of Survivin (also known as BIRC5 or IAP4) and activation of caspases-3 and -7 following USP1 knockdown or inhibition in the absence of external DNA damage stimuli. Notably, EWS cells display hypersensitivity to combinatorial treatment of doxorubicin or etoposide, EWS standard of care drugs, and USP1 inhibitor compared to single agents alone. Together, our study demonstrates that USP1 is regulated by EWS-FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes EWS cells to standard of care chemotherapy.

2024-01-26 | PXD041033 | Pride

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