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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.

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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.

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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.

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