Identification of YAP-Dependent High-Grade Complex Karyotype Sarcomas
The current management of localized high-grade sarcomas is based on histology. Yet, clinically, within subtypes there exists a spectrum of disease. To improve treatments of sarcoma and decrease the development of recurrent disease, targeted therapy approaches are needed. To optimize this, molecular subtypes with specific therapeutic vulnerabilities should be identified. Yes-associated protein (YAP), the key transcriptional regulator of the Hippo signaling pathway is amplified across a subset of high-grade sarcomas, not isolated to a specific histology. YAP cooperates with transcriptional coactivators to drive gene networks critical to proper cellular development and differentiation. High-expression or activation of YAP is associated with poor patient prognosis in high-grade complex karyotype sarcomas. Our lab has identified YAP as a potent driver of sarcoma development in a forward genetics model system. Using this system, we can identify key downstream YAP targets and validate these. This can be integrated into YAP gene signatures and human sarcoma data to identify a subset of sarcomas that rely on YAP signaling in the absence of an amplification. There are treatments in development and clinical trials targeting YAP and the Hippo signaling pathway. We anticipate that a subset of sarcomas will be sensitive to these new therapeutics.
The goal of this project is to identify and predict human sarcomas that can be effectively treated with Hippo targeting treatments. To do this, we will first identify key downstream YAP targets and validate these as mediators of YAP driven sarcomas. This information will be used to inform the development of a sarcoma specific YAP transcriptional signature. We will then validate this signature across a panel of sarcomas by treating with YAP inhibitors and determining the ability of this signature to predict response to treatment. The signature can then be refined based on the results of these experiments. The proposed research will result in a clinically applicable YAP signature that can be further validated in vivo prior to translation.