Abstract 2139: Hippo pathway transcriptional coactivators YAP/TAZ in soft tissue and bone tumors

Introduction: Soft tissue and bone tumors represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is continuously increasing, specific findings on altered signal transduction pathways as a basis for molecularly targeted therapeutic strategies is still sparse. Given recent studies on aberrant activation of the Hippo pathway transcriptional coactivators YAP and TAZ in different cancer types, the aim of this study was to determine the involvement of YAP/TAZ-mediated signal transduction in soft tissue and bone tumors. Experimental procedures: The expression levels of nuclear YAP and TAZ were analyzed by immunohistochemistry in a large cohort of 486 soft tissue and bone tumors. The comprehensive set of tissue specimens comprised 10 diagnostic categories: Angiosarcomas (AS; n=29), Ewing’s sarcomas (ES; n=20), leiomyosarcomas (LMS; n=68), malignant peripheral nerve sheath tumors (MPNST; n=45), solitary fibrous tumors (SFT; n=36), synovial sarcomas (SySa; n=65), well-differentiated liposarcomas (WDLS; n=55), dedifferentiated liposarcomas (DDLS; n=74), myxoid liposarcomas (MLS; n=85), and pleomorphic liposarcomas (PLS; n=9). The biological effects of the small molecule YAP/TAZ-TEAD inhibitor verteporfin on sarcoma cell proliferation (MPNST, SySa and MLS) were monitored by immunoblotting and cell viability assays in vitro. Results: Moderate to strong nuclear staining of YAP and TAZ was detected in 53% and 33% of soft tissue and bone tumor specimens, respectively. YAP nuclear expression was most prevalent in MPNST (58%), SySa (78%) and MLS (91%), whereas nuclear TAZ was predominately found in AS (55%), MLS (55%) and MPNST (71%). Immunoblotting confirmed the nuclear localization of YAP and TAZ in MPNST, SySa and MLS cell lines. Inhibition of the transcriptionally active YAP/TAZ-TEAD interaction employing the small molecular inhibitor verteporfin resulted in a significant suppression of sarcoma cell viability. Conclusions: This study identifies elevated transcriptional activity of nuclear YAP/TAZ as specific liability of subgroups of soft tissue and bone tumors. We provide preclinical evidence that YAP/TAZ-mediated signal transduction represents a rational target for therapeutic intervention in sarcoma cell lines that warrants further investigation. Citation Format: Ilka Isfort, Sandra Elges, Magdalene Cyra, Danielle Brandes, Ruth Berthold, Marcus Renner, Gunhild Mechtersheimer, Olle Larsson, Sebastian Huss, Eva Wardelmann, Wolfgang Hartmann, Marcel Trautmann. Hippo pathway transcriptional coactivators YAP/TAZ in soft tissue and bone tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2139.