Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy

Abstract

Oncogenesis in synovial sarcoma is driven by the chromosomal translocation t(X,18; p11,q11), which generates an in-frame fusion of the SWI/SNF subunit SS18 to the C-terminal repression domains of SSX1 or SSX2. Proteomic studies have identified an integral role of SS18-SSX in the SWI/SNF complex, and provide new evidence for mistargeting of polycomb repression in synovial sarcoma. Two recent in vivo studies are highlighted, providing additional support for the importance of WNT signaling in synovial sarcoma: One used a conditional mouse model in which knockout of β-catenin prevents tumor formation, and the other used a small-molecule inhibitor of β-catenin in xenograft models.

Significance: Synovial sarcoma appears to arise from still poorly characterized immature mesenchymal progenitor cells through the action of its primary oncogenic driver, the SS18-SSX fusion gene, which encodes a multifaceted disruptor of epigenetic control. The effects of SS18-SSX on polycomb-mediated gene repression and SWI/SNF chromatin remodeling have recently come into focus and may offer new insights into the basic function of these processes. A central role for deregulation of WNT-β-catenin signaling in synovial sarcoma has also been strengthened by recent in vivo studies. These new insights into the the biology of synovial sarcoma are guiding novel preclinical and clinical studies in this aggressive cancer.

Figure 1

Protein interaction domains involved in synovial sarcoma translocations, where SS18 is fused to one of highly paralogous SSX1 or SSX2 genes. Translocation breakpoints (vertical arrowheads) result in the fusion of almost all SS18 sequence to the carboxy terminal region of SSX protein. Protein domains: SNH, SS18 N-terminal homology; QPGY, glutamine/proline/glycine/tyrosine-enriched domain; KRAB, Kruppel-associated box domain; DD, divergent domain; RD, repression domain; NLS nuclear localization signal. A conserved site for ubiquitin modification at lysine 13 of SS18 is shown (K13Ub), as well as a site of ubiquitin/acetyl modification at lysine 124 of SSX1.

Figure 2

Putative mechanisms for autocrine/paracrine activation of Wnt signaling in synovial sarcoma. Wnt signals through FZZD/LRP6, inhibiting the APC/AXIN/GSK3/CSNK1 destruction complex, leading to release and nuclear transport of beta catenin (CTNNB1). SS18/SSX integrates within SWI/SNF complexes, with potential interactions with developmental pathways including Notch/Hes, BMP/Smad, Hedghog/GLI, MAPK/ETS, and LEF1/TLE1. Extensive cross-regulation between developmental pathways may lead to transcriptional activation of Wnt ligands and/or de-repression of Wnt target genes. The site of action of Wnt inhibitors PRI-724 and LGK974 are indicated.

Figure 3

Drug targets downstream of receptor tyrosine kinases involved in synovial sarcoma (RTK). Extensive cross-talk and feedback regulation are observed in pro-survival signaling through MAPK/ERK and AKT/MTOR pathways. Intrinsic drug resistance to monotherapies can be mediated by activation of prosurvival signaling in either pathway, due to removal of inhibitory feedback (red lines). Drug targets discussed in the text are shown in green. BH3 represents pro-apoptotic BH3-domain-only proteins, and their activation by stress activated protein kinases is shown (SAPK: JNK, p38). Dashed lines represent nuclear export and translation of mRNA to protein.