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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

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Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma [scRNA-Seq]

Project description:Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS.

2024-11-08 | GSE281096 | GEO

Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma

2024-11-10 | GSE281529 | 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

Genetic Screen in a Pre-Clinical Model of Sarcoma Development Defines Drivers and Therapeutic Vulnerabilities

Project description:High-grade complex karyotype sarcomas are a heterogeneous group of more than seventy tumors that vary in histology, clinical course, and patient demographics. Despite these differences, these high-grade sarcomas are treated similarly with varying outcomes. Pre-clinical models of distinct human sarcoma subtypes would advance insights into the relationships between sarcomas and inform therapeutic decisions. We describe the transformation of human mesenchymal stem cells into multiple subtypes of high-grade sarcoma. Using a pooled genetic screening approach, we identified key drivers and potential modifiers of transformation. YAP1, KRAS, CDK4, and PIK3CA were validated as drivers of four distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), leiomyosarcoma (LMS), and osteosarcoma (OS). Histologically and phenotypically these tumors reflect human sarcomas including the pathognomonic complex karyotype and YAP1 amplification. Transcriptome analysis confirmed that these tumors accurately recapitulate human disease. This model is a tool that can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes and to identify and test new therapeutic targets for this aggressive and heterogeneous disease.

2024-08-15 | GSE228213 | GEO

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

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