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SS18-SSX–Dependent YAP/TAZ Signaling in Synovial Sarcoma

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SS18-SSX–Dependent YAP/TAZ Signaling in Synovial Sarcoma Published OnlineFirst February 27, 2019; DOI: 10.1158/1078-0432.CCR-17-3553 Translational Cancer Mechanisms and Therapy Clinical Cancer Research SS18-SSX–Dependent YAP/TAZ Signaling in Synovial Sarcoma Ilka Isfort1,2, Magdalene Cyra1,2, Sandra Elges2, Sareetha Kailayangiri3, Bianca Altvater3, Claudia Rossig3,4, Konrad Steinestel2,5, Inga Grunewald€ 1,2, Sebastian Huss2, Eva Eßeling6, Jan-Henrik Mikesch6, Susanne Hafner7, Thomas Simmet7, Agnieszka Wozniak8,9, Patrick Schoffski€ 8,9, Olle Larsson10, Eva Wardelmann2, Marcel Trautmann1,2, and Wolfgang Hartmann1,2 Abstract Purpose: Synovial sarcoma is a soft tissue malignancy Results: Asignificant subset of synovial sarcoma characterized by a reciprocal t(X;18) translocation. The chi- showed nuclear positivity for YAP/TAZ and their tran- meric SS18-SSX fusion protein acts as a transcriptional dysre- scriptional targets FOXM1 and PLK1. In synovial sarco- gulator representing the major driver of the disease; however, ma cells, RNAi-mediated knockdown of SS18-SSX led to the signaling pathways activated by SS18-SSX remain to be significant reduction of YAP/TAZ-TEAD transcriptional elucidated to define innovative therapeutic strategies. activity. Conversely, SS18-SSX overexpression in SCP-1 Experimental Design: Immunohistochemical evaluation cells induced aberrant YAP/TAZ-dependent signals, mech- of the Hippo signaling pathway effectors YAP/TAZ was per- anistically mediated by an IGF-II/IGF-IR signaling loop formed in a large cohort of synovial sarcoma tissue specimens. leading to dysregulation of the Hippo effectors LATS1 SS18-SSX dependency and biological function of the YAP/TAZ and MOB1. Modulation of YAP/TAZ-TEAD–mediated Hippo signaling cascade were analyzed in five synovial sarco- transcriptional activity by RNAi or verteporfintreatment ma cell lines and a mesenchymal stem cell model in vitro. YAP/ resulted in significant growth inhibitory effects in vitro TAZ-TEAD–mediated transcriptional activity was modulated and in vivo. by RNAi-mediated knockdown and the small-molecule inhib- Conclusions: Our preclinical study identifies an elementary itor verteporfin. The effects of verteporfin were finally tested in role of SS18-SSX–driven YAP/TAZ signals, highlights the com- vivo in synovial sarcoma cell line-based avian chorioallantoic plex network of oncogenic signaling pathways in synovial membrane and murine xenograft models as well as a patient- sarcoma pathogenesis, and provides evidence for innovative derived xenograft. therapeutic approaches. 1Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Munster€ University Hospital, Munster,€ Germany. 2Gerhard-Domagk-Institute of Pathology, Munster€ University Hospital, Munster,€ Germany. 3Department of Introduction € Pediatric Hematology and Oncology, University Children's Hospital Munster, Synovial sarcoma (SySa) is an aggressive malignancy com- Munster,€ Germany. 4Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), prising approximately 2% of all sarcomas with a predomi- University of Munster,€ Munster,€ Germany. 5Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany. 6Department of Med- nance in adolescents and young adults (1, 2). Wide surgical icine A, Hematology, Oncology and Respiratory Medicine, University Hospital resection, radiotherapy, and chemotherapy with ifosfamide Munster,€ Munster,€ Germany. 7Institute of Pharmacology of Natural Products & and doxorubicin represent established therapeutic options; Clinical Pharmacology, Ulm University, Ulm, Germany. 8Laboratory of Experi- however, prognosis in the metastatic situation is poor (3–5). mental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. fi 9 Speci c molecularly targeted therapeutic approaches are cur- Department of General Medical Oncology, University Hospitals Leuven, Leuven rently limited. Cancer Institute, Leuven, Belgium. 10Departments of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden. The molecular hallmark of SySa is a pathognomonic reci- procal t(X;18)(p11;q11) translocation, leading to the fusion Note: Supplementary data for this article are available at Clinical Cancer of SS18 (SYT) and one of the homologues SSX genes Research Online (http://clincancerres.aacrjournals.org/). (most frequently SSX1 or SSX2,inrarecasesSSX4), generating M. Trautmann and W. Hartmann contributed equally to this article. chimeric SS18-SSX fusion proteins (6–8). Although the SS18- Corresponding Authors: Wolfgang Hartmann and Marcel Trautmann, Division SSX protein is known to play a crucial role in SySa tumorigen- € of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Munster esis, its specific biological function and its mechanism of þ University Hospital, Domagkstr. 17, 48149, Germany. Phone: 49 (0) 251-83- action remain to be elucidated. Neither SS18 and the SSX 58479 and -57623, Fax: þ49 (0) 251-83-57559. E-mail: [email protected] and [email protected] proteins, nor the chimeric SS18-SSX oncoproteins feature known DNA-binding motifs; however, they have been reported Clin Cancer Res 2019;25:3718–31 to contribute to the dysregulation of gene expression through doi: 10.1158/1078-0432.CCR-17-3553 association with SWI/SNF and Polycomb chromatin remodel- Ó2019 American Association for Cancer Research. ing complexes (8–12). 3718 Clin Cancer Res; 25(12) June 15, 2019 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst February 27, 2019; DOI: 10.1158/1078-0432.CCR-17-3553 YAP/TAZ Signals in Synovial Sarcoma Translational Relevance Materials and Methods Tumor specimens and tissue microarray Acting as a powerful transcriptional dysregulator, the chi- SySa tissue microarrays (TMA, containing two representative meric SS18-SSX fusion protein constitutes the major onco- 1-mm cores) were prepared from formalin- fixed, paraffin- genic driver of synovial sarcoma. Given the notorious diffi- embedded tumor specimens selected from the archive of the culty to target the fusion protein itself, functional insights into Gerhard-Domagk-Institute of Pathology, Muenster University SS18-SSX–shaped tumor biology are essential to decipher Hospital, essentially as described previously (19). Two areas druggable tumor vulnerabilities. We here describe a molecu- within each tumor were selected by experienced pathologists larly based mechanism of YAP/TAZ activation in synovial (E. Wardelmann, W. Hartmann) to represent potential heteroge- sarcoma effected by the SS18-SSX fusion protein that involves neity. Necrobiotic areas and their neighborhood were excluded an IGF-II/IGF-IR signaling loop, leading to dysregulation of from TMA sampling to avoid the detection of secondary (e.g., the Hippo effectors LATS1 and MOB1 and provide evidence of hypoxia-induced) alterations. All diagnoses were reviewed by high efficacy of a YAP/TAZ–directed therapeutic approach in three experienced pathologists (S. Huss, S. Elges and W. Hart- synovial sarcoma in vitro and in vivo. Our study highlights the mann) according to the current WHO classification of tumours of complex network of oncogenic signaling pathways in synovial Soft Tissue and Bone (2), based on morphologic and immuno- sarcoma pathogenesis and refines the concept of biologically histochemical criteria, FISH or RT-PCR analysis. In total, 65 SySa founded molecular strategies to inhibit SS18-SSX–driven tissue specimens were included in the study (30/46.2% female, tumorigenesis. 35/53.8% male; median age at diagnosis was 45 years, range 8–78 years). Forty-eight tumors belong to the monophasic subtype, 14 to the biphasic subtype, and 3 tumors were classified as poorly differentiated SySa. Median tumor size was 5 cm (range 0.3–20 The YAP/TAZ Hippo signaling pathway is an evolutionarily cm). In all cases, FISH or RT-PCR analysis confirmed the diagnosis conserved pathway essential in the control of tissue homeostasis of SySa, revealing the pathognomonic t(X;18) translocation as and organ size through the regulation of cell proliferation, apo- described previously (20). Clinicopathologic characteristics of the ptosis, and stem cell self-renewal (13–15). The central component cohort are summarized in Table 1. The study was approved by the is a kinase module comprising the serine-threonine kinases Ethics Committee of the University of Munster€ (2015-548-f-S) MST1/2 and LATS1/2, complemented by the adaptor proteins SAV1 and MOB1 to control the transcriptional co-activators YAP and TAZ. While in their non-phosphorylated state YAP and TAZ translocate to the nucleus and interact with TEAD1-4 transcription Table 1. Clinicopathologic characteristics of the cohort of SySa patients (n ¼ 65) factors to induce expression of target genes such as CTGF, CYR61, Age (years) PLK1 and FOXM1, LATS1/2-mediated phosphorylation of YAP/ Mean (ÆSD) 41 (Æ17) – TAZ results in their cytoplasmic retention and proteasomal deg- Median (range) 45 (8 78) <41 28 (43.1%) radation (14, 16). 41 37 (59.9%) Although convincing data on the oncogenic function of YAP/ Type TAZ signals in several epithelial tumors are available (13), only Primary tumor 43 (66.2%) little is known about their role in malignant soft tissue tumors. Metastasis 9 (13.8%) First evidence for a function of YAP/TAZ in mesenchymal tumor- Recurrence 7 (10.8%) igenesis was gathered by St John and colleagues who demonstrat- ND 6 (9.2%) fi Histology ed that approximately 15% of LATS1/2-de cient mice develop Monophasic 48 (73.9%) metastasizing spindle-cell sarcomas
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