Abstract A02: Targeting EWS-FLI1 dose-dependent epithelial-to-mesenchymal transition

Reversible transitions from a proliferative to a nonproliferative but highly migratory and invasive phenotype, widely known as epithelial-to-mesenchymal transition (EMT), is a prerequisite for wound healing and organ development but also a hallmark of cancer. Recently, phenotypic changes resembling EMT were described to occur in Ewing sarcoma upon modulation of expression of the driver oncogene EWS-FLI1. Evidence was provided for the presence of highly migratory EWS-FLI1-low cells in Ewing sarcoma cell lines as well as in about 20% of primary tumors at low frequency (Franzetti et al., 2017). Importantly, when injected into the tail vein of immunosuppressed mice, EWS-FLI1-low cells were more likely to result in lung metastases than EWS-FLI1-high cells upon re-expression of the oncogene. In our study, we identified a mechanism for the cytoskeletal reprograming underlying EWS-FLI1 dose-dependent phenotypic transitions in Ewing sarcoma. We provide evidence for EWS-FLI1 blocking access of the transcriptional coactivators MRTFB and TAZ to the YAP/TEAD transcription factor complex on enhancers of EWS-FLI1 anti-correlated genes. Upon modulation of EWS-FLI1 expression, TEADs get activated downstream of Rho signaling through recruitment of MRTFB/YAP/TAZ, leading to the expression of key cytoskeletal components and regulators involved in the reorganization of the actin cytoskeleton. Based on these findings, we hypothesized that small-molecule inhibitors of the YAP/TAZ/TEAD pathway should interfere with the migratory phenotype of EWS-FLI1-low cells. In fact, the YAP/TAZ inhibitor verteporfin (Visudyne®), which is clinically used as a photosensitive drug in the treatment of age-related macular degeneration, was able to block Ewing sarcoma cell migration at low nanomolar concentrations without affecting tumor cell proliferation. These results suggest that YAP/TAZ inhibitors may be considered as a promising add-on to conventional combination treatments to prohibit tumor cell dissemination and metastasis. Citation Format: Anna M. Katschnig, Maximilian O. Kauer, Raphaela Schwentner, Eleni M. Tomazou, Dave N.T. Aryee, Heinrich Kovar. Targeting EWS-FLI1 dose-dependent epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A02.