Abstract B03: The EWS/FLI oncogene exerts pro-migratory and anti-apoptotic effects via dysregulation of focal adhesion kinase (FAK) signaling in Ewing sarcoma

Abstract

Abstract Ewing sarcoma (ES), an aggressive bone tumor of childhood and adolescence, is one of the most genetically normal tumors. The oncogenic potential is derived from chimeric fusions of EWS and ETS family transcription factors, with EWS-FLI1 rearrangements in 85% of cases. (Micro-) metastatic dissemination is the major threat for patients, and earlier studies have shown that cytoskeletal rearrangements upon EWS/FLI oncoprotein expression contribute to a migratory phenotype in ES cells. Using a patient-derived ES cell line with a stable EWS/FLI knockdown (A673-iEF), we show here that key tumorigenic effects of EWS/FLI are mediated via autophosphorylation of FAK on tyrosine 397, resulting in enhanced formation of focal adhesions and actin stress fibers as well as tumor cell migration, but impaired caspase-3-mediated anoikis (detachment-induced cell death) in vitro. This effect was not limited to A673 cells, but could also be observed in TC-32 and CADO-ES1 ES cells. Application of the FAK inhibitor 1, 2, 4, 5-Benzenetetraamine tetrahydrochloride (Y15) impaired cell migration and enhanced caspase-mediated apoptosis. Taken together, our results show that key oncogenic effects of EWS rearrangements are mediated via FAK autophosphorylation in ES and provide a rationale for the use of FAK inhibitors to impair metastatic dissemination of ES. Citation Format: Konrad Steinestel, Marcel Trautmann, Jan Rehkaemper, Eva Wardelmann, Uta Dirksen, Wolfgang Hartmann. The EWS/FLI oncogene exerts pro-migratory and anti-apoptotic effects via dysregulation of focal adhesion kinase (FAK) signaling in Ewing sarcoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B03.