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Generation and characterization of a novel mouse model of synovial sarcoma

University of British Columbia

Synovial sarcoma is an aggressive soft-tissue sarcoma that most frequently affects adolescents and young adults and can arise in virtually any area of the body. The biologic behaviour of synovial sarcoma can vary depending on several factors and the 10-year survival rate has been estimated at only 50%. Synovial sarcoma is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation which produces a fusion oncogene named SS18-SSX. The cell of origin of synovial sarcoma is currently unknown, although recent research indicates that it may arise from a mesenchymal stem/progenitor cell population. We have generated a unique mouse model of synovial sarcoma where the human SS18-SSX fusion oncogene is conditionally expressed in a population of mesenchymal progenitor cells using a Hic1Cʳᵉᴱᴿᵀ² driver developed by our lab. This model shows robust formation of synovial sarcoma with 100% penetrance and a mean latency period of 16 weeks. The mouse tumours were characterized histologically, using immunofluorescence and hematoxylin and eosin staining, and at the transcriptomic level using single-cell RNA-sequencing. Histologic analysis reveals characteristic cellular morphology and marker expression, while scRNA-seq analyses show that gene expression in these tumours parallels transcript profiles observed in human synovial sarcoma samples. Using this model, we can identify and isolate early neoplastic lesions prior to the development of grossly visible tumours; scRNA-seq of early lesions shows a partially-transformed phenotype and highlights cellular programs involved early in sarcomagenesis. We then generated two modified versions of this model through the addition of stabilized β-catenin (Ctnnb1ᴱˣ³Fᴵ) and knockout of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (Smarcb1Fᴵ) to assess the effects of activated WNT/ β-catenin signaling and loss of Smarcb1, respectively. Both models show a decreased latency period and more aggressive phenotype and provide additional support for the roles of the WNT/ β-catenin pathway and chromatin remodeling complexes in synovial sarcomagenesis. Overall, these models identify Hic1+ mesenchymal progenitors as a putative cell of origin for synovial sarcoma and provide us with a unique opportunity to address the molecular and cellular mechanisms underlying synovial sarcomagenesis.

Text

2024-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71350

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/