A mouse model for synovial sarcoma has enabled scientists to make tremendous progress toward understanding the origin and pathogenesis of this highly aggressive soft-tissue malignancy.
The research, published in the April issue of the journal Cancer Cell, published by Cell Press, provides new information about the timing and environment required for initiation and progression of synovial sarcoma.
The mouse model is also likely to serve as an invaluable resource for development of successful therapeutic strategies for this often lethal cancer.
Synovial sarcoma is associated with expression of a chimeric fusion protein called SYT-SSX. Dr. Mario R. Capecchi, from the Howard Hughes Medical Institute and the Department of Human Genetics at the University of Utah School of Medicine, and colleagues developed a mouse model that expresses human SYT-SSX in chosen target cells. Using this approach, the researchers discovered that, although it is named for its common proximity to limb joints, this tumor appears to arise from skeletal muscle precursor cells called myoblasts. Remarkably, expression of SYT-SSX in myoblasts was sufficient to induce synovial sarcoma with an astonishing 100% penetrance.
Use of a sophisticated conditional genetic technique allowed the researchers to control the timing of fusion protein expression so as to examine what happens when the protein is expressed at different stages of muscle development. Earlier expression of SYT-SSX disrupted normal development and was associated with embryonic lethality, while expression in more differentiated muscle cells induced significant muscle cell damage and death in the absence of tumor formation.
Further studies demonstrated that this mouse model of synovial sarcoma faithfully recapitulates human synovial sarcoma on multiple levels. As in the human cancer, tumors in the mice arise most commonly in close proximity to joints. The researchers speculate that the cartilage associated with joints may contribute to a favorable microenvironment for the SYT-SSX-expressing cells.
Taken together, these observations provide new information about the source of synovial sarcoma and illustrate the importance of timing and the tissue microenvironment in disease progression, reinforcing the usefulness of conditional genetic studies for modeling cancer. “This mouse model of synovial sarcoma should significantly aid our efforts in understanding the pathogenesis of this disease and serve as a useful preclinical platform to design and evaluate therapeutic modalities,” explains Dr. Capecchi.