Abstract 3437: Requirement for YAP1 signaling in myxoid liposarcoma
Authors: Trautmann Marcel , Cheng Ya-Yun , Jensen Patrizia , Azoitei Ninel , Brunner Ines , Hüllein Jennifer , Slabicki Mikolaj , Isfort Ilka , Cyra Magdalene , Wardelmann Eva , Huss Sebastian , Altvater Bianca , Rossig Claudia , Hafner Susanne , Simmet Thomas , Ståhlberg Anders , Åman Pierre , Zenz Thorsten , Lange Undine , Kindler Thomas , Scholl Claudia , Hartmann Wolfgang , Fröhling Stefan 
Published: August 2019

Myxoid liposarcomas (MLS) account for 20% of malignant adipocytic tumors and are characterized by a high rate of local recurrence and development of distant metastases in approximately 40% of patients. Most MLS are driven by the FUS-DDIT3 fusion gene encoding an aberrant transcription factor. The mechanisms whereby FUS-DDIT3 mediates sarcomagenesis are incompletely understood, and strategies to selectively target MLS cells remain elusive. In this study, we employed genome-scale RNA interference (RNAi) screening to uncover that human mesenchymal stem cells engineered to express FUS-DDIT3 and MLS cell lines are dependent on YAP1, a transcriptional co-activator and central effector of the Hippo pathway involved in tissue growth and tumorigenesis. Analysis of a large cohort of primary MLS specimens (n=223) revealed that nuclear YAP1 expression was significantly more prevalent in MLS compared to other liposarcoma subtypes. In support of the concept that increased YAP1-mediated transcriptional activity represents an essential feature of MLS development, RNAi-based YAP1 depletion in cultured MLS cells resulted in suppression of cell viability, cell cycle arrest, cellular senescence, and induction of apoptosis accompanied by decreased YAP1 target gene expression, and YAP1-positive primary MLS tumors showed strong expression of YAP1 downstream effectors such as FOXM1 and PLK1. Mechanistically, FUS-DDIT3 promotes YAP1 transcription, nuclear localization, and transcriptional activity and physically associates with YAP1 in the nucleus of MLS cells, pointing to the coordinate establishment of gene expression programs that promote MLS tumorigenesis. Consistent with the hypothesis that a YAP1-directed therapeutic approach could represent a rational strategy to selectively target FUS-DDIT3-expressing MLS cells, pharmacologic inhibition of YAP1 activity with verteporfin suppressed cell viability and YAP1 target gene expression in MLS cell lines, and the growth-inhibitory effects of YAP1 knockdown or verteporfin treatment could be recapitulated in MLS cell line-based xenograft models. Collectively, our data identify dependence on aberrant YAP1 activity as specific liability of FUS-DDIT3-expressing MLS cells, and provide preclinical evidence that YAP1-mediated signal transduction represents a candidate target for therapeutic intervention that warrants further investigation.

Citation Format: Marcel Trautmann, Ya-Yun Cheng, Patrizia Jensen, Ninel Azoitei, Ines Brunner, Jennifer Hüllein, Mikolaj Slabicki, Ilka Isfort, Magdalene Cyra, Eva Wardelmann, Sebastian Huss, Bianca Altvater, Claudia Rossig, Susanne Hafner, Thomas Simmet, Anders Ståhlberg, Pierre Åman, Thorsten Zenz, Undine Lange, Thomas Kindler, Claudia Scholl, Wolfgang Hartmann, Stefan Fröhling. Requirement for YAP1 signaling in myxoid liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3437.