Targeting wnt in synovial sarcoma models.
Synovial sarcoma (SS) is the second most common soft-tissue tumor in children and adolescents after rhabdomyosarcoma. The first case of a fetal synovial sarcoma was recently reported. Synovial sarcoma most frequently develops in the soft tissues of the joints, but is also known to appear in other organs such as the kidney. It is an aggressive tumor with a very high five year-mortality rate and for which no curative therapy exists.
Synovial sarcoma is characterized by a unique and recurrent genetic rearrangement between chromosome 18 and the X chromosome. This event occurs in over 90% of the cases and results in the generation of SYT-SSX, a protein thought to be actively involved in the initiation and development of the cancer. Since it is uniquely present in SS, SYT-SSX represents a good target for anti-cancer therapy. Understanding its biological function is therefore imperative for designing curative drugs for the disease.
We have found that SYT-SSX2 activates b-catenin, mediator of Wnt, a major signaling pathway frequently involved in carcinogenesis. Moreover, specific inhibition of Wnt/?-catenin activity led to delayed growth of primary SS cells. Importantly, we observed that SYT-SSX2 prevented cells from undergoing normal differentiation. Differentiation arrest is one key feature of cancer cells in which active Wnt is often implicated. In this proposal we intend to define b-catenin/Wnt contribution to synovial sarcoma development and characterize the Wnt pathway as a rational candidate target to combat synovial sarcoma.