The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE148724 | GEO | 2020/12/21
REPOSITORIES: GEO
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Project description:Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.
| S-EPMC7768195 | biostudies-literature
Project description:Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and Polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose Polycomb Repressor Complex (PRC) 2 activity while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of Polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and confer vulnerability to USP7 loss, a core member of ncPRC1.1. SyS organoids thus provide a powerful model to define mechanisms of epigenetic dysregulation on which SyS cells are dependent.
2020-12-21 | GSE148723 | GEO
Project description:Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and Polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose Polycomb Repressor Complex (PRC) 2 activity while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of Polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and confer vulnerability to USP7 loss, a core member of ncPRC1.1. SyS organoids thus provide a powerful model to define mechanisms of epigenetic dysregulation on which SyS cells are dependent.
2020-12-21 | GSE148722 | GEO
Project description:The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.
| PRJNA625495 | ENA
Project description:The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies [RNA-seq]
| PRJNA625497 | ENA
Project description:The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies [ChIP-seq]
| PRJNA625498 | ENA
Project description:ObjectivePrimary pulmonary synovial sarcoma (PPSS) is extremely rare. This study aims to identify the clinicopathologic and therapeutic factors determining survival in PPSS.MethodsWe performed a retrospective analysis of 121 patients from the Surveillance, Epidemiology, and End Results Database as well as 12 patients from our own institution diagnosed with PPSS. Patient survival was evaluated using the Kaplan-Meier method.ResultsThe median survival time for 12 PPSS patients in our institution was 78 months. Postoperative chemotherapy (P = .027 for overall survival and P = .035 for disease-specific survival) was associated with superior survival, whereas pneumonectomy (P = .011 for overall survival and P = .006 for disease-specific survival) was associated with worse survival. Single lobe involvement (P = .022) and the absence of lymph node involvement (P = .045) were associated with improved disease-specific survival and overall survival, respectively. In the Surveillance, Epidemiology, and End Results Database, the median survival time was 23 months. Significantly superior survival was observed in patients with earlier American Joint Committee on Cancer stage (Ⅰ-Ⅱ) (P < .001 for both overall survival and disease-specific survival). Patients who were diagnosed within the recent decade did not achieve a better survival (P = .599 for overall survival and P = .596 for disease-specific survival).ConclusionsPPSS was aggressive with a very poor prognosis. The seventh American Joint Committee on Cancer stage might aid in predicting survival. Pneumonectomy and lymph node involvement might be associated with worse survival, whereas single lobe involvement and postoperative chemotherapy might be associated with improved survival.
| S-EPMC9390693 | biostudies-literature
Project description:Synovial Sarcomas (SS) are a type of Soft Tissue Sarcoma (STS) and represent 8-10% of all STS cases. Although SS can arise at any age, it typically affects younger individuals aged 15-35 and is therefore part of both pediatric and adult clinical practices. SS occurs primarily in the limbs, often near joints, but can present anywhere. It is characterized by the recurrent pathognomonic chromosomal translocation t(X;18)(p11.2;q11.2) that most frequently fuses SSX1 or SSX2 genes with SS18. This leads to the expression of the SS18-SSX fusion protein, which causes disturbances in several interacting multiprotein complexes such as the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, also known as the BAF complex and the Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). Furthermore, this promotes widespread epigenetic rewiring, leading to aberrant gene expression that drives the pathogenesis of SS. Good prognoses are characterized predominantly by small tumor size and young patient age. Whereas, high tumor grade and an increased genomic complexity of the tumor constitute poor prognostic factors. The current therapeutic strategy relies on chemotherapy and radiotherapy, the latter of which can lead to chronic side effects for pediatric patients. We will focus on the known roles of SWI/SNF, PRC1, and PRC2 as the main effectors of the SS18-SSX-mediated genome modifications and we present existing biological rationale for potential therapeutic targets and treatment strategies.
| S-EPMC6813544 | biostudies-literature
Project description:Primary cardiac synovial sarcomas are very rare, representing <1% of all primary cardiac tumors. We report the case of a 19-year-old man with syncope and dynamic obstructive shock caused by a large right-sided intracardiac tumor. (Level of Difficulty: Beginner .).
| S-EPMC9434647 | biostudies-literature
Project description:Synovial sarcoma is the most common pediatric non-rhabdomyosarcoma soft tissue sarcoma and accounts for about 8-10% of all soft tissue sarcoma in childhood and adolescence. The presence of a chromosomal translocation-associated SS18-SSX-fusion gene is causally linked to development of primary synovial sarcoma. Metastases occur in approximately 50-70% of synovial sarcoma cases with yet unknown mechanisms, which led to about 70-80% mortality rate in five years. To explore the possibilities to investigate metastatic mechanisms of synovial sarcoma, we carried out the first genome-wide search for potential genetic biomarkers and drivers associated with metastasis by comparative mutational profiling of 18 synovial sarcoma samples isolated from four patients carrying the primary tumors and another four patients carrying the metastatic tumors through whole exome sequencing. Selected from the candidates yielded from this effort, we examined the effect of the multiple missense mutations of ADAM17, which were identified solely in metastatic synovial sarcoma. The mutant alleles as well as the wild-type control were expressed in the mammalian cells harboring the SS18-SSX1 fusion gene. The ADAM17-P729H mutation was shown to enhance cell migration, a phenotype associated with metastasis. Therefore, like ADAM17-P729H, other mutations we identified solely in metastatic synovial sarcoma may also have the potential to serve as an entry point for unraveling the metastatic mechanisms of synovial sarcoma.
| S-EPMC6305143 | biostudies-literature