The functional role of the YAP/TAZ Hippo signaling pathway transducers and their WNT/β‑catenin interdependence in synovial sarcomas

• Applicant: Professor Dr. Wolfgang Hartmann
• Subject Area: Pathology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398417454

Synovial sarcomas are malignant mesenchymal tumors genetically characterized by a specific reciprocal translocation t(X;18)(p11;q11). The translocation results in a gene fusion leading to the expression of chimeric SS18‑SSX transcriptional regulators that activate oncogenic signaling pathways. We and others recently detected SS18-SSX-dependent activation of WNT/beta-catenin signals in synovial sarcomas which were shown to be essential in tumorigenesis. Beyond that, own preliminary data make proof of an activation of the Hippo signaling pathway transducers YAP/TAZ in synovial sarcomas. While in epithelial cells the close interdependence of YAP/TAZ- and WNT-signals is well documented, in synovial sarcomas, the functional and clinical role of YAP/TAZ-signals and the relationship of YAP/TAZ- and WNT-signals have not been understood. • The first part of the project therefore analyzes the biological and clinico-pathological relevance of expression patterns of elementary effectors, regulators and targets of the Hippo-YAP/TAZ- and WNT-signaling cascades in a large cohort of synovial sarcomas. • The comprehensive second part is dedicated to the detailed functional analysis of SS18-SSX-dependent regulation/interdependence of YAP/TAZ- and WNT-signals in synovial sarcomas in vitro. Particular emphasis is put on the analysis of the signaling pathways´ interconnection with regard to mechanisms of activation and inactivation.• The third part of the project employs specific small molecule inhibitors and RNAi-based approaches to investigate the response of synovial sarcoma cells to an inhibition of YAP/TAZ- and WNT-signals in vitro and in vivo using chicken chorioallantoic membranes and murine xenografts. As in the previous parts of the project, a particular focus will be put on the interdependence of the signaling pathways.The molecular results of the project will significantly contribute to the understanding of the biology of synovial sarcomas and will provide fundaments for the establishment of innovative, molecularly targeted therapeutic concepts.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Marcel Trautmann