Abstract 1049: Targeting YAP/TAZ pathway inhibits Ewing sarcoma metastasis

Abstract

Abstract The term epithelial to mesenchymal transition (EMT) and its reverse (MET) describe the dynamic and reversible metamorphosis of cells from a highly organized to a loose migratory phenotype through cytoskeletal reorganization causing cellular plasticity. EMT/MET are inherent to normal embryonal development and wound healing, but cancer cells hijack the underlying mechanisms to enable oscillations between proliferation, invasion and migration that cause metastasis, the major killer of cancer patients. Recently, fluctuations of the oncoprotein EWS-FLI1 were identified to drive EMT/MET in Ewing sarcoma. We previously demonstrated that, in presence of EWS-FLI1, transcriptional co-activators MRTFB and TAZ are largely blocked from associating with TEAD and its target genes keeping tumor cells in a poorly migratory, highly proliferative state. In contrast, under EWS-FLI-low conditions, MRTFB and TAZ associate with YAP/TEAD complexes on chromatin resulting in cytoskeletal target gene activation and phenotypic transition to a highly migratory and low proliferative state. We therefore hypothesized that pharmacologic inhibition of YAP/TAZ/TEAD protein interaction should prevent Ewing sarcoma cells from EMT and consequently interfere with their metastatic potential. Verteporfin is a small molecule safely used in the treatment of age-related macular degeneration. Independent of its photosensitizing activity exploited in ophthalmology, it is a YAP/TAZ pathway -blocking compound. In vitro treatment of EWS-FLI1-low Ewing sarcoma cells with verteporfin resulted in decreased YAP/TAZ/TEAD complex formation in the nanomolar range, reversal of the de-repression of a EWS-FLI1 controlled EMT transcriptional signature, and inhibition of tumor cell migration in a Boyden chamber assay. Upon orthotopic implantation of TC71 Ewing sarcoma cells into the tibial crest of SCID beige mice, intra-peritoneal treatment of mice with 25mg verteporfin/kg/day before and after amputation of the affected limb led to a drastic decrease of lung metastases without affecting primary tumor growth and without obvious general toxicity. Therefore, YAP/TAZ pathway blockade holds promise as a potential metastasis-preventive strategy in the treatment of Ewing sarcoma patients with primary localized disease. Citation Format: Lisa Bierbaumer, Anna M. Katschnig, Branka Radic-Sarikas, Jeffrey R. Petro, Karin Mühlbacher, Dave N. Aryee, Anna R. Pötsch, Sandra Högler, Lukas Kenner, Aykut Uren, Heinrich Kovar. Targeting YAP/TAZ pathway inhibits Ewing sarcoma metastasis [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 1049.