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

Lesley A. Hill, R. Wilder Scott, Lauren A. Martin, Martin Arostegui, George Davenport, Marcos Vemon, Jakob Hofvander, Xue Qi Wang, Jinxiu Li, Torsten O. Nielsen, Kevin B. Jones, Martin Hirst and T. Michael Underhill ()
Additional contact information
Lesley A. Hill: Biomedical Research Centre
R. Wilder Scott: Biomedical Research Centre
Lauren A. Martin: Biomedical Research Centre
Martin Arostegui: Biomedical Research Centre
George Davenport: Biomedical Research Centre
Marcos Vemon: Biomedical Research Centre
Jakob Hofvander: Lund University, Division of Clinical Genetics, Department of Laboratory Medicine
Xue Qi Wang: University of British Columbia and BC Cancer, Department of Pathology
Jinxiu Li: University of Utah, Department of Orthopaedics
Torsten O. Nielsen: University of British Columbia and BC Cancer, Department of Pathology
Kevin B. Jones: University of Utah, Department of Orthopaedics
Martin Hirst: BC Cancer Agency, Michael Smith Genome Sciences Centre
T. Michael Underhill: Biomedical Research Centre

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy that is characterised 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. A mesenchymal stromal cell (MSC) specific CreERT2 line was employed 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 exhibited high concordance with human synovial sarcoma subtypes at the histological and molecular levels. Genetic refinement of the cell-of-origin revealed that synovial sarcomas derive from a rare Hic1+ Pdgfra+ Lgr5+ fibroblastic population. Furthermore, comparative transcriptomic analysis revealed 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 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 SyS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

Date: 2025
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DOI: 10.1038/s41467-025-65850-5

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