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The fibroblast epigenome underlies SS18::SSX-mediated transformation in synovial sarcoma
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The fibroblast epigenome underlies SS18::SSX-mediated transformation in synovial sarcoma
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Journal Article
The fibroblast epigenome underlies SS18::SSX-mediated transformation in synovial sarcoma
2025
Overview
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.
The cellular origin of soft-tissue cancers, such as synovial sarcoma (SyS), is unknown. Here, expression of the oncoprotein, SS18::SSX, in fibroblasts was sufficient to produce human-like SyS tumours, thereby identifying a cell of origin for SyS.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/51
/ 14/19
/ 14/63
/ 38/15
/ 38/39
/ 38/91
/ 64/110
/ Animals
/ Cell Transformation, Neoplastic - genetics
/ Embryos
/ Female
/ Gene Expression Regulation, Neoplastic
/ Histones
/ Humanities and Social Sciences
/ Humans
/ Latency
/ Medical Genetics and Genomics (including Gene Therapy)
/ Medicinsk genetik och genomik (Här ingår: Genterapi)
/ Medicinska och farmaceutiska grundvetenskaper
/ Mesenchymal Stem Cells - metabolism
/ Mesenchymal Stem Cells - pathology
/ Mice
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ Proteins
/ Sarcoma
/ Sarcoma, Synovial - genetics
/ Sarcoma, Synovial - metabolism
/ Sarcoma, Synovial - pathology
/ Science
/ Tumors
