Beta-catenin activation in synovial sarcomagenesis and progression
Synovial sarcoma is a deadly soft-tissue malignancy with a predilection for adolescents and young adults. The development of sorely needed targeted therapies depends on the identification of critical pathways in synovial sarcomagenesis. Expression of an SYT-SSX fusion oncogene generated by one of the characteristic X:18 translocations initiates synovial sarcomagenesis. Possible cooperation of ß-catenin has been implicated by the prominent nuclear localization of ß-catenin in a majority of human synovial sarcomas and the identification of activating ß-catenin exon 3 mutations in a subset of these. The mixed cellular phenotype of synovial sarcoma, including both mesenchymal and epithelial features, further suggests a role for Wnt/ß-catenin deregulation. Using the genetically engineered mouse model of synovial sarcoma developed in our laboratory, we will interrogate the contributions of ß-catenin activation and disruption to synovial sarcoma initiation as well as maintenance and progression. The previously described model, which spontaneously generates tumors that faithfully recapitulate human synovial sarcoma at complete penetrance via the conditional expression of the human SYT-SSX2 cDNA in myoblasts, has recently been improved to permit in vivo monitoring of tumor maintenance and progression. In addition, a more stringent model for site-specific synovial sarcomagenesis using adenoviral delivery of Cre-recombinase permits the investigation of tumor initiation itself. These two models will be further manipulated by crossing them to available mice with conditional genetic alterations that constitutively activate or ablate the ß-catenin gene. In addition, two ß-catenin antagonists, PKF115-584 and AV6946, and one ß-catenin activator, lithium chloride, will be used to test the role of transient enhancement or disruption of the pathway in synovial sarcoma initiation, maintenance, and progression. Our preliminary data suggests that ß-catenin activation indeed enhances synovial sarcomagenesis. By these experiments, we will bring its role and its potential as a therapeutic target into better focus.