The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies

Abstract

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.

An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma

“…8) thereby reinforcing its oncogenic activity. This model is in agreement with a previous study showing that RYBP occupancy is induced by SS18-SSX expression in murine mesenchymal stem cells 78 . The feedback loop we identified is also reminiscent of the role of RYBP in the PRC1 complex, where it both promotes interactions within the complex leading to increased complex stability 70 and recognizes and binds H2AK119ub1-modified nucleosomes to further promote H2AK119ub1 deposition 79 .…”

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

“…Tumoroid models of pediatric nephroblastoma (Wilms' tumor) have been described, which, depending on the subtype, can contain stromal cells (Calandrini et al , 2020). In addition, cells derived from synovial sarcoma and other adult soft tissue sarcomas can grow to a limited extent on fetal calf serum, which, although undefined in terms of the required essential growth factors, also indicates feasibility (Brodin et al , 2019; Boulay et al , 2021). Furthermore, in vitro propagation of RMS tumor cells derived from patient‐derived xenograft (PDX) mouse models has recently been shown (Manzella et al , 2020).…”

FUS oncofusion protein condensates recruit mSWI/SNF chromatin remodeler via heterotypic interactions between prion‐like domains

“…SSXRD domain is a protein–protein interaction module that directly interacts with the polycomb complex DNA‐binding protein, KDM2B 69 . Not surprisingly, SS18‐SSX fusions recruit mSWI/SNF complex to KDM2B‐binding genomic loci and result in the aberrant activation of numerous otherwise repressed genes 69,70 . Therefore, similar to the FUS PLD , it is likely that SS18 PLD is capable of recruiting mSWI/SNF chromatin remodelers via SS18 PLD ‐SWI/SNF PLD interactions.…”