Reversing mSWI/SNF (BAF) Complex Misassembly and Genomic Targeting in Human Synovial Sarcoma
Synovial sarcoma (SS) represents the most common non-rhabdomyosarcomatous soft-tissue malignancy in pediatric patients; 30% of all SS manifest during the first two decades of life with a median age of 13 years. These aggressive tumors are largely resistant to conventional chemotherapy-based treatments, underscoring the need to understand the disease development and identify therapeutic approaches. SS tumors are uniformly characterized (essentially 100% of patients) by a genetic event called chromosomal translocation which results in two proteins being abnormally fused together. This translocation causes the addition of a segment of a protein called “SSX” to a protein called “SS18,” which is a member of a large protein complex in the nucleus of our cells called the BAF complex. BAF complexes function to alter the architecture of our genomes and allow for timely and appropriate gene expression.
We recently demonstrated that the SS18-SSX fusion preferentially binds to and disrupts the composition and function of these complexes, favoring tumor development. Remarkably, we have found that this is dynamic and reversible; normal complexes can be reformed and proliferation is ceased if SSX and its interactions are blocked. The work proposed will provide novel insights regarding the mechanism underlying SS18-SSX-mediated activity and has potential to lead to the development of highly specific targeted therapeutics for this intractable cancer.