Abstract 960: Deregulation of the Hippo pathway in soft tissue sarcoma promotes FOXM1 expression and tumorigenesis

The genetic aberrations responsible for soft tissue sarcoma formation in adults are largely unknown, and targeted therapies are sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft tissue sarcomas, resulting in elevated expression of the effector molecule YAP. Based on data gathered from human sarcoma patients, we concluded that more than 40% of human sarcomas have lost one or more copies of upstream HIPPO pathway regulators including SAV1, LATS2, and NF2. Loss of these molecules deactivates the HIPPO pathway, permitting uncontrolled proliferation and growth. Expression of active YAP is the direct result of this copy number loss and we have found YAP to be elevated in primary human fibrosarscomas, liposarcomas, and pleomorphic tumors. Pharmacologic inhibition of YAP significantly impaired primary sarcomagenesis in a murine allograft model. Using a novel autochthonous mouse model and mechanistic analyses in human and murine sarcoma cells, we determined that YAP-dependent expression of the transcription factor, FOXM1, is necessary for sarcoma cell proliferation and tumorigenesis. FOXM1 expression is elevated in multiple human soft tissue sarcoma subtypes. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in co-regulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of sarcomas. Citation Format: T.S. Karin Eisinger, Vera Mucaj, Kevin Biju, Michael Nakazawa, Mercy Gohil, Timothy Cash, Sam Yoon, Nicolas Skuli, Kyung Min park, Sharon Gerecht, Celeste Simon. Deregulation of the Hippo pathway in soft tissue sarcoma promotes FOXM1 expression and tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 960. doi:10.1158/1538-7445.AM2015-960