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Super-enhancer analysis of human sarcomas reveals YAP1 control of NF-κB-dependent tumorigenesis [RNA-seq]

ABSTRACT: Recent sequencing efforts have failed to identify consistent oncogenic driver mutations in most adult soft tissue sarcomas. Therefore, we investigated alternate genetic/epigenetic mechanisms underlying sarcomagenesis to facilitate development of novel therapeutics. Our previous work showed that deregulation of the Hippo pathway increases proliferation in many types of sarcoma. We have now identified the mechanism of Hippo-mediated sarcomagenesis using autochthonous mouse models, ChIP-seq (H3K27Ac) and super-enhancer (SE) analysis of human undifferentiated pleomorphic sarcoma (UPS), an aggressive muscle-derived tumor. We found that the Hippo effector, Yes-Associated Protein 1 (YAP1) enhances NF-êB signaling and that YAP1 is constitutively active in these tumors due to epigenetic silencing of its inhibitor Angiomotin (AMOT). Treatment with epigenetic modulators (SAHA and JQ1) inhibited YAP1 transcription and restored expression of AMOT. These changes initiated a muscle differentiation program and reduced tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97296 | GEO | 2018/03/01

REPOSITORIES: GEO

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Super-enhancer analysis of human sarcomas reveals YAP1 control of NF-κB-dependent tumorigenesis [ChIP-seq]

Project description:Recent sequencing efforts have failed to identify consistent oncogenic driver mutations in most adult soft tissue sarcomas. Therefore, we investigated alternate genetic/epigenetic mechanisms underlying sarcomagenesis to facilitate development of novel therapeutics. Our previous work showed that deregulation of the Hippo pathway increases proliferation in many types of sarcoma. We have now identified the mechanism of Hippo-mediated sarcomagenesis using autochthonous mouse models, ChIP-seq (H3K27Ac) and super-enhancer (SE) analysis of human undifferentiated pleomorphic sarcoma (UPS), an aggressive muscle-derived tumor. We found that the Hippo effector, Yes-Associated Protein 1 (YAP1) enhances NF-êB signaling and that YAP1 is constitutively active in these tumors due to epigenetic silencing of its inhibitor Angiomotin (AMOT). Treatment with epigenetic modulators (SAHA and JQ1) inhibited YAP1 transcription and restored expression of AMOT. These changes initiated a muscle differentiation program and reduced tumorigenesis.

2018-03-01 | GSE97295 | GEO

Expression analysis of YAP and Angiomotin target genes

Project description:To assess changes in gene expression regulated by Yap1 or Angiomotin, either Yap1 or Angiomotin were knocked down in HEK293 cells using shRNA and expression was assessed by microarray analysis and compared to expression patterns of wildtype cells. Microarray analysis was performed to compare gene expression in Amot-KD, Yap-KD, and control HEK293 cells. Samples from three individual experiments for each of the three groups were analyzed.

2013-10-21 | E-GEOD-49406 | biostudies-arrayexpress

Expression data from murine sarcomas

2013-10-11 | GSE46836 | GEO

Expression data from murine sarcomas

Project description:The cell of origin for rhabdomyosarcoma (RMS) and undifferentiated pleomorphic sarcoma (UPS) remains to be determined. We utilized two skeletal muscle specific inducible Cre mouse lines to transform both skeletal muscle stem cells and progenitors to determine which cells give rise to RMS and UPS. Both P7KP and MDKP derived mice were injected with systemic tamoxifen and mice were euthanized after tumor development. Sections of resected tumor were placed in RNAlater and placed at -80 until RNA isolation. RNA was isolated by grinding up tumor sections in liquid nitrogen and using the Qiagen RNEasy Micro kit.

2013-10-11 | E-GEOD-46836 | biostudies-arrayexpress

High throughput profiling of undifferentiated pleomorphic sarcomas identifies two main subgroups with distinct immune contexture, clinical outcome and sensitivity to targeted therapies

Project description:Undifferentiated pleomorphic sarcoma (UPS) is the most frequent, aggressive and less-characterized sarcoma subtype. This study aims to assess UPS molecular characteristics and identify specific therapeutic targets.

| EGAS00001004612 | EGA

Undifferentiated pleomorphic sarcoma recapitulates the expressional profile of Subtype II Leiomyosarcoma

Project description:Background: Undifferentiated pleomorphic sarcoma (UPS), used to be called malignant fibrous histiocytoma (MFH), is a malignant soft tissue tumor of uncertain origin, and is characterized by morphology. UPS often share similar morphological characters with other sarcomas, especially Leiomyosarcoma. Leiomyosarcoma (LMS) is another malignant soft tissue sarcoma with complex genomic abnormalities, origin from smooth muscle. As a result, development of gene signature and/or biomarkers distinguishing UPS and LMS will definitely help the pathologist to precisely diagnose those patients. However, in the past, UPS was reported to be indistinguishable with LMS by genomic profiles. Methods and Results: In this study, 3’ end RNA Sequencing (3SEQ) was used to expression profile 6 UPS and 99 LMS cases. Overall, UPS was undistinguished with LMS by 3SEQ data, however, when we stratified LMS into three subtypes, UPS was shown to share similar expression pattern with Subtype II LMS, but had distinct molecular expression patterns with Subtype I and Subtype III LMS. Additional Immunohistochemistry staining by using LMS Subtype I and Subtype II markers validated that UPSs were positive for Subtype II marker ARL4C, but negative for Subtype I marker LMOD1. Furthermore, CD4 was shown to be significantly more highly expressed in UPS than LMS in both mRNA and protein levels. Conclusion: This study first reported that UPS shared similar gene expression pattern with subtype II LMS and UPS recapitulated the expression profiles of subtype II LMS. In this study, 3’ end RNA Sequencing (3SEQ) was used to expression profile 6 UPS and 99 LMS cases. In order to explore the molecular differences between UPS and LMS, We analyzed the expression data by SAMseq to identify the genes which were significantly differently expressed between UPS and LMS, between UPS and each LMS subtype.

2015-05-19 | E-GEOD-53844 | biostudies-arrayexpress

Shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma of the extremities

Project description:Soft tissue sarcoma diagnostics and prognostics are challenging, particularly in highly malignant and pleomorphic subtypes such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). We applied 32K BAC-arrays and gene expression profiling to 18 extremity soft tissue LMS and 31 extremity soft tissue UPS with the aim to identify molecular subtype signatures and genomic prognostic markers. Both the gains/losses and gene expression signatures revealed striking similarities between UPS and LMS, which were indistinguishable using unsupervised hierarchical cluster analysis and significance analysis for microarrays. Gene expression analysis revealed just 9 genes, among them Tropomyosin beta, that were differentially expressed. Loss of 4q31 (encompassing the SMAD1 locus), loss of 18q22 and tumor necrosis were identified as independent predictors of metastasis in multivariate stepwise Cox regression analysis. Combined analysis applying loss of 4q31 and 18q22 and presence of necrosis improved the area under receiver operating characteristic curve for metastasis prediction from 0.64 to 0.86. The extensive genetic similarities between extremity soft tissue UPS and LMS suggest a shared lineage of these STS subtypes and the new and independent genetic prognosticators identified hold promise for refined prognostic determination in high-grade, genetically complex STS. Genomic DNA was extracted from a total of 49 samples, 31 Undifferentiated pleomorphic Sarcomas and 18 Leiomyosarcomas. The DNA was labeled using Bioprime array CGH labeling kit (Invitrogen). Promega pooled male DNA was used as reference. Labeled DNA was hybridized onto BAC arrays containing ~32 000 BAC clones printed in singlets. BAC arrays were produced at the SWEGENE DNA Microarray Facility at Lund University.

2010-10-08 | E-GEOD-13775 | biostudies-arrayexpress

Expression analysis of YAP and Angiomotin target genes

2013-10-21 | GSE49406 | GEO

Undifferentiated pleomorphic sarcoma recapitulates the expressional profile of Subtype II Leiomyosarcoma

2015-05-19 | GSE53844 | GEO

Single cell RNA sequencing data of Side Population and Non-Side Population tumor cells from a mouse model of undifferentiated pleomorphic sarcoma

Project description:We report the application of single-cell RNA sequencing data on Side Population (SP) cells and their Non-Side Population (NSP) counterparts in a mouse model of undifferentiated pleomorphic sarcoma (UPS). SP cells exhibit tumor propagting cell properties characterized by enhanced tumorigenicity and self-renewal potential. The purpose of this experiment is to investigate cellular heterogeneity at the gene expression level in UPS tumors and lineage relationships between different subpopulation of tumor cells. We generated the gene expression profiles of individual cells in the SP and NSP compartments of mouse UPS.

2022-01-07 | GSE162847 | GEO

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