Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells
Jared J. Barrott, … , Mario R. Capecchi, Kevin B. Jones
Jared J. Barrott, … , Mario R. Capecchi, Kevin B. Jones
Published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):207-218. https://doi.org/10.1172/JCI94955.
View: Text | PDF
Research Article Development Oncology

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells

Abstract

Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5–expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of β-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2–transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX–driven oncogenesis in cells as differentiated as preosteoblasts.

Authors

Jared J. Barrott, Benjamin E. Illum, Huifeng Jin, Matthew L. Hedberg, Yanliang Wang, Allie Grossmann, Malay Haldar, Mario R. Capecchi, Kevin B. Jones

×

Figure 3

Synovial sarcomagenesis induced by Myf5Cre is restricted to its embryonic, multipotent lineage, not postnatal muscle progenitors.

Options: View larger image (or click on image) Download as PowerPoint
Synovial sarcomagenesis induced by Myf5Cre is restricted to its embryoni...
(A) Schematic of inducible alleles in mice, which depend on Cre-mediated recombination of the rtTA and the TetO promoter–controlled SS18-SSX2 allele (hSS2T), plus the presence of doxycycline for expression of the fusion oncogene. (B) Fluorescence photomicrographs showing some GFP from the recombination of rtTA and more GFP from the activation of hSS2T in embryonic fibroblasts in culture. Scale bars: 100uM. (C) Schematic and Kaplan-Meier plots of the absence of tumorigenesis in 5 groups with noted genotypes and doxycycline or postnatal induction with tamoxifen as well as rates of tumorigenesis in 2 groups with embryonic induction of SS18-SSX2 expression (n = 25 per group; log-rank test Z score = 4.48 aænd P < 0.001, comparing 2 mg and 1 mg dosing). (D) Gross image, (E) GFP fluorescence image, and (F) H&E histology photomicrographs of a limb tumor that developed in a 6-month-old Myf5Cre hSS2T mouse after embryonic initiation of doxycycline (1 mg/ml). Open arrowheads indicate biphasic histologic features of mucinous gland formation. Scale bar: 100 μm.