Interplay of YAP1 and β-catenin with SS18::SSX and BAF complexes in synovial sarcoma

• Applicants: Professor Dr. Stefan Fröhling; Professor Dr. Wolfgang Hartmann; Dr. Ilka Isfort
• Subject Area: Pathology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398417454

Synovial sarcoma (SySa) tumorigenesis is driven by the integration of its pathognomonic SS18::SSX fusion protein into BAF chromatin remodeling complexes, resulting in changes in BAF complex composition, its recruitment to chromatin and thus dysregulation of gene transcription. The detailed mechanism of SS18::SSX-mediated BAF complex dysregulation is not well understood but essential to understand SySa tumorigenesis and to establish molecularly guided therapies. Given our previous data on a high prevalence of YAP1 and β catenin expression in SySa tissues, their respective interaction with BAF complex subunits and their BAF- and SS18::SSX-dependent transcriptional activation, we hypothesize that the interplay of YAP1 and β-catenin with SS18::SSX and BAF complexes is crucial for BAF complex dysregulation and the realization of SS18::SSX´s oncogenic function. To this end, we will (1) correlate expression patterns of YAP1, β-catenin and BAF complex subtypes in primary SySa tissues, (2) decipher the role of YAP1 and β catenin for altered BAF complex assembly, (3) analyze joint functioning of BAF complexes with YAP1, β catenin and SS18::SSX through the identification of shared interaction partners, as well as assessment of their genome-wide co-localization and RNA expression profiles, and (4) re-transfer our findings on the oncogenic complex formation to primary tumor specimens. This project will provide essential insights in SySa biology as a basis for novel therapeutic approaches.

• DFG Programme: Research Grants