An inducible ectopic expression system of EWSR1-FLI1 as a tool for understanding Ewing sarcoma oncogenesis

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.Research in the EDA lab is supported by Asociación Española Contra el Cáncer (AECC). Enrique de Alava’s lab is also supported by the Ministry of Economy and Competitiveness of Spain-FEDER (CIBERONC, PI11700464, RD06/0020/0059) and the European Commission (FP7-HEALTH-2011-two-stage, Project ID278742 EUROSARC). DGD and LHP are supported by CIBERONC (CB16/12/00361). DGD is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016). LHP is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI-0013-2018). The funder Vitro SA provided support in the form of salaries for the author CM but had no additional roles in the study design, data collection, data analyses, decision to publish or manuscript preparation. The specific roles of this author (CM) are articulated in the ‘author contributions’ section