Abstract
BackgroundEWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing's sarcoma family tumors (ESFT) and is thought to initiate the development of the disease. Previous genomic profiling experiments have identified EWS-FLI1–regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1–dependent molecular functions characterizing this aggressive cancer is lacking.Methodology/Principal FindingsIn this study, a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT. Out of 80 normal tissues tested, mesenchymal progenitor cells (MPC) were found to fit the hypothesis that EWS-FLI1 is the driving transcriptional force in ESFT best and were therefore used as the reference tissue for the construction of the molecular function map. The interrelations of molecular pathways were visualized by measuring the similarity among annotated gene functions by gene sharing. The molecular function map highlighted distinct clusters of activities for EWS-FLI1 regulated genes in ESFT and revealed a striking difference between EWS-FLI1 up- and down-regulated genes: EWS-FLI1 induced genes mainly belong to cell cycle regulation, proliferation, and response to DNA damage, while repressed genes were associated with differentiation and cell communication.Conclusions/SignificanceThis study revealed that EWS-FLI1 combines by distinct molecular mechanisms two important functions of cellular transformation in one protein, growth promotion and differentiation blockage. By taking MPC as a reference tissue, a significant EWS-FLI1 signature was discovered in ESFT that only partially overlapped with previously published EWS-FLI1–dependent gene expression patterns, identifying a series of novel targets for the chimeric protein in ESFT. Our results may guide target selection for future ESFT specific therapies.
Highlights
Ewing’s sarcoma family tumors (ESFT), which comprise Ewing’s sarcoma, peripheral primitive neuroectodermal tumors, and Askin tumor, are undifferentiated small blue round cell tumors affecting children and young adults as the second most frequent bone cancer [1]
The assumption that most gene expression aberrations in ESFT with respect to the cell of origin are triggered by EWS-FLI1 provides a model with which it is possible to test the quality of any reference tissue
While the correlations were generally biased towards negative values (Figure 1), the highest inverse correlation was found for the comparison of differences between EWS-FLI1 knockdown and control (DKD) with DET from the comparison of ESFT with mesenchymal progenitor cells (MPC) as reference tissue (DET[MPC], r = 20.5)
Summary
Ewing’s sarcoma family tumors (ESFT), which comprise Ewing’s sarcoma, peripheral primitive neuroectodermal tumors, and Askin tumor, are undifferentiated small blue round cell tumors affecting children and young adults as the second most frequent bone cancer [1]. This highly aggressive cancer is characterized by a chromosomal translocation that results in the formation of a gene fusion between the EWSR1 locus and an ETS transcription factor gene, which in 85% of the cases is FLI1 [2]. Previous genomic profiling experiments have identified EWS-FLI1–regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1–dependent molecular functions characterizing this aggressive cancer is lacking
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