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The fibroblast epigenome underlies SS18::SSX-mediated transformation in synovial sarcoma

ABSTRACT: Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy that is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene named SS18::SSX. Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. Here we employ a mesenchymal stromal cell (MSC) specific CreERT2 line to express SS18::SSX in fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 ± 2.8 weeks. Murine tumours exhibit high concordance with human synovial sarcoma subtypes at the histological and molecular levels1. Genetic refinement of the cell-of-origin reveal that synovial sarcomas derive from a rare Hic1+ Pdgfra+ Lgr5+ fibroblastic population. Furthermore, comparative transcriptomic analysis reveals the acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequent unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibite overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminates in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SyS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE213265 | GEO | 2025/09/11

REPOSITORIES: GEO

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The fibroblast epigenome underlies SS18::SSX-mediated transformation in synovial sarcoma

Project description:Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy that is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene named SS18::SSX. Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. Here we employ a mesenchymal stromal cell (MSC) specific CreERT2 line to express SS18::SSX in fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 ± 2.8 weeks. Murine tumours exhibit high concordance with human synovial sarcoma subtypes at the histological and molecular levels1. Genetic refinement of the cell-of-origin reveal that synovial sarcomas derive from a rare Hic1+ Pdgfra+ Lgr5+ fibroblastic population. Furthermore, comparative transcriptomic analysis reveals the acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequent unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibite overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminates in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SyS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

2025-09-11 | GSE216769 | GEO

Cell-of-origin epigenome underlies SS18::SSX-mediated transformation [RNA-seq]

Project description:Synovial sarcoma is an aggressive soft-tissue malignancy that is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene namedSS18::SSX. Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. A mesenchymal stromal cell (MSC) specific CreERT2 line was employed to expressSS18::SSXin fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 ± 2.5 weeks. Murine tumours exhibited high concordance with human synovial sarcoma sub-types at the histological and molecular levels1. Genetic refinement of the cell-of-origin revealed that synovial sarcomas derive from a rareHic1+Pdgfra+Lgr5+fibroblastic population. Furthermore, longitudinal multi-omic profiling along the transformation continuum revealed the step-wise acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequently, the gradual unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibited overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminated in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

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Cell-of-origin epigenome underlies SS18::SSX-mediated transformation [ChIP-seq]

2025-09-11 | GSE270369 | GEO

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies [RNA-seq]

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

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies [ChIP-seq]

2020-12-21 | GSE148722 | GEO

A stage-specific induction system reveals that the oncogenic fusion protein in synovial sarcoma, SS18-SSX, is a cellular context-dependent epigenetic modifier

Project description:We analyzed the effects of cellular context on the function of the synovial sarcoma-specific fusion protein, SS18-SSX, using human pluripotent stem cells containing the drug-inducible SS18-SSX gene. To investigate the cell-type-dependent effecfts of SS18-SSX, we performed gene expression profiling experiments. Comparison of global gene expressions of hPSCs, hPSC-NCCs, and hPSC-MSCs with or without the inductuion of SS18-SSX2

2016-04-13 | E-GEOD-63895 | biostudies-arrayexpress

SS18::SSX redistributes BAF chromatin remodelers selectively to activate and repress transcription [RNA-Seq]

Project description:Synovial sarcoma (SS) is a rare malignancy, involves a t(X;18) chromosomal translocation that creates a fusion gene SS18-SSX. SS18 is a chromatin remodeling BAF-complexes component, which incorporated in CBAF and GBAF (non-canonical ncBAF). Our previous studies determined that incorporation of the fusion oncoprotein caused degradation of CBAF complexes, emphasizing a critical oncogenic function of GBAF and PBAF in synovial sarcomagenesis. To determine the SyS dependencies on different subtypes of BAF complexes during tumor development in vivo, we used our SyS mouse model combined with genetic disruption of specific BAF complexes components ARID1A/B or PBRM1. In this study, our fundings suggest that depletion of ARID1A and ARID1B sped tumorigenesis, without significant change in the histomorphology of the developing tumors. Loss of PBRM1 also led to faster tumor growing, but Pbrm1-silenced tumors lacked the full array of SyS histomorphologies observed in wildtype tumors. Overall, Arid1a or Arid1b disruption rendered tumor transcriptomes that clustered within the hSS2 tumor transcriptomes, unlike Pbrm1 disrupted tumors.

2025-06-10 | GSE269772 | GEO

SS18::SSX redistributes BAF chromatin remodelers selectively to activate and repress transcription [ChIP-Seq, Hi-ChIP]

Project description:In order to evaluate SS18::SSX distribution across chromatin in synovial sarcoma, we performed ChIP-seq from mouse SyS tumors expressing the human SS18::SSX2 using an antibody specific for the fusion oncoprotein SS18::SS. ChIP-seq was also employed to assess SyS genome profiles of specific chromatin histone marks (H2AK119ub, H3K4me1, H3K4me3, H3K27ac and H3K27me3), and chromatin conformation by HiChIP was evaluated using an antibody against H3K27ac to identify enhancer loops for the purpose of assigning distal regulatory elements to specific genes. Furthermore, we also characterize the distribution of each BAF family subtypes with ChIP-seq ( ARID1A (cBAF), DPF2 (cBAF), PBRM1 (PBAF) and BRD9 (GBAF/non-canonical BAF)). In this study, our fundings suggest that SS18::SSX distributes to proximal and distal regulatory elements bearing ubiquitylated histone 2A and GBAF distributes with the fusion to broad proximal and distal regions; CBAF and PBAF distribute narrowly to active transcriptional start sites.

2025-06-10 | GSE269770 | GEO

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-driven transcription, resulting in DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying a therapeutic vulnerability in SS.

2025-08-07 | PXD059936 | Pride

Opposing genetic and immune mechanisms shape oncogenic programs in synovial sarcoma

Project description:Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA-seq (scRNA-seq), spatial profiling, genetic and pharmacological perturbations. scRNA-Seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune deprived niches in situ and marks tumors with poor clinical outcomes in three independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/6 inhibitors. This drug combination enhanced malignant cell immunogenicity in SyS models, leading to induced T cell reactivity and T-cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

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