Wnt Signaling and Synovial Sarcoma

Synovial sarcoma is a tumor of multipotential or partly committed stem cell origin, as evidenced by its phenotypic, spatial and molecular heterogeneity. The SYT-SSX (SS18-SSX) fusion transcript characterizes this malignancy. This most frequently is either SYT-SSX1 (SS18-SSX1) or SYT-SSX2 (SS18-SSX2). Rarely a SYT-SSX4 (SS18-SSX4) fusion occurs. Gene expression analysis demonstrated that SYT-SSX2 upregulates mediators of developmental pathways including Wnt, Notch, TGFβ, hedgehog and fibroblast growth factor in human mesenchymal stem cells. In synovial sarcoma SYT-SSX2 also directly activates canonical Wnt/β-catenin signaling in preclinical studies. The Wnt signaling pathway is activated and the downstream effector β-catenin accumulates within the nucleus in 28% - 57% of clinical cases. In a potential therapeutic advance, a small molecule Wnt antagonist LGK-974 inhibits palmitoylation of Wnt by targeting the membrane bound acyltransferase Porcupine. Palmitoylation is a requirement for Wnt ligand availability. Potential future molecular treatment strategies include Wnt pathway antagonism, optimization of pathway inhibition by combinatorial therapeutics and integrating Wnt inhibition with other therapeutics such as fibroblast growth factor receptor inhibitors.