title: SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma.
abstract: Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/β-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/β-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear β-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/β-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/β-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/β-catenin protein-protein interaction significantly blocked the canonical Wnt/β-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/β-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/β-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.
authors.affiliation: 1] Department of Pathology, University Hospital Cologne, Cologne, Germany [2] Department of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Trautmann
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Sievers
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Aretz
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kindler
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Michels
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Friedrichs
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Renner
authors.affiliation: Department of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kirfel
authors.affiliation: Department of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Steiner
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Huss
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Departments of Oncology & Pathology, The Karolinska Institute, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Division of Orthopaedic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kawai
authors.affiliation: Laboratory of Molecular & Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Laboratory Medicine, Chungoku Central Hospital, Fukuyama, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sonobe
authors.affiliation: Department of Neuropathology, University Hospital Bonn, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Waha
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Mechtersheimer
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013584:Sarcoma, Synovial / Q000188:drug therapy / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C538948:CGP049090; C495270:CTNNB1 protein, human; D015514:Oncogene Proteins, Fusion; C538949:PKF115-584; C548732:PKF118-310; D011744:Pyrimidinones; C587877:SS18-SSX1 fusion protein; C116512:SYT-SSX fusion protein; D014227:Triazines; D051176:beta Catenin; D010569:Perylene