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

Hill, Lesley A. ; Scott, R. Wilder ; Martin, Lauren A. ; Arostegui, Martin ; Davenport, George ; Vemon, Marcos ; Hofvander, Jakob LU ; Wang, Xue Qi ; Li, Jinxiu and Nielsen, Torsten O. , et al. (2025) In Nature Communications 16(1).
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... (More)

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.

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Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
issue
1
article number
10830
publisher
Nature Publishing Group
external identifiers
  • scopus:105023554613
  • pmid:41330912
ISSN
2041-1723
DOI
10.1038/s41467-025-65850-5
language
English
LU publication?
yes
id
ed1a5b30-7f18-426c-8a99-9f4038de9c61
date added to LUP
2026-01-14 11:34:49
date last changed
2026-01-15 03:00:17
@article{ed1a5b30-7f18-426c-8a99-9f4038de9c61,
  abstract     = {{<p>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<sup>+</sup>Pdgfra<sup>+</sup>Lgr5<sup>+</sup> 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.</p>}},
  author       = {{Hill, Lesley A. and Scott, R. Wilder and Martin, Lauren A. and Arostegui, Martin and Davenport, George and Vemon, Marcos and Hofvander, Jakob and Wang, Xue Qi and Li, Jinxiu and Nielsen, Torsten O. and Jones, Kevin B. and Hirst, Martin and Underhill, T. Michael}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The fibroblast epigenome underlies SS18::SSX-mediated transformation in synovial sarcoma}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-65850-5}},
  doi          = {{10.1038/s41467-025-65850-5}},
  volume       = {{16}},
  year         = {{2025}},
}