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

滑膜肉瘤是一种恶性间叶肿瘤，其遗传学特征为特异性相互易位t（X;18）（p11;q11）。易位导致基因融合，导致嵌合SS 18-SSX转录调节因子的表达，从而激活致癌信号通路。我们和其他人最近检测到滑膜肉瘤中WNT/β-连环蛋白信号的SS 18-SSX依赖性激活，这在肿瘤发生中是必不可少的。除此之外，我们的初步数据证明了Hippo信号转导通路雅普/TAZ在滑膜肉瘤中的激活。虽然在上皮细胞中雅普/TAZ-和WNT-信号的密切相互依赖性已被充分证明，但在滑膜肉瘤中，雅普/TAZ-信号的功能和临床作用以及雅普/TAZ-和WNT-信号的关系尚未被理解。· 因此，该项目的第一部分分析了一个大型滑膜肉瘤队列中Hippo-YAP/TAZ和WNT信号级联的基本效应物、调节物和靶点表达模式的生物学和临床病理学相关性。· 全面的第二部分致力于详细的功能分析的SS 18-SSX依赖性调节/相互依存的雅普/TAZ-和WNT-信号在滑膜肉瘤在体外。特别强调的是放在信号通路的相互联系的激活和失活机制的分析。 该项目的第三部分采用特定的小分子抑制剂和基于RNAi的方法，研究滑膜肉瘤细胞对雅普/TAZ-和WNT-信号抑制的反应，在体外和体内使用鸡绒毛尿囊膜和小鼠异种移植物。本项目的前几部分将特别关注信号通路的相互依赖性，其分子结果将有助于对滑膜肉瘤生物学的理解，并将为建立创新的分子靶向治疗概念提供基础。

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.