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Overcoming resistance to conventional drugs in Ewing’s sarcoma and identification of molecular predictors of outcome.

ABSTRACT: The improvement of Ewing's sarcoma (EWS) therapy is currently linked to find strategies to select patients with poor and good prognosis at diagnosis and to generate modified treatment regimens. In this study, we analyze the molecular factors governing EWS response to chemotherapy in order to identify genetic signatures that may be used for risk-adapted therapy. Keywords: Gene Expression Analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE12102 | GEO | 2008/07/15

SECONDARY ACCESSION(S): PRJNA113791

REPOSITORIES: GEO

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Project description:EWS-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 be the initiating event in the development of the disease. Previous genomic profiling experiments have identified a number of 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. In this study a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments on a uniform microarray platform 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 tumors. Based on the assumption that EWS-FLI1 is the driving transcriptional force in ESFT pathogenesis, we predicted an inverse correlation of gene expression for EWS-FLI1 regulated genes between the putative tissue of origin and the cell lines under EWS-FLI1 knockdown conditions. Consistent with recent reports, mesenchymal progenitor cells (MPC) were found to fit this hypothesis best and were therefore used as the reference tissue for the construction of the molecular function map in ESFT. 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. This 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. Keywords: Ewing's Sarcoma, EWS-FLI1, RNAi knock down and controls

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Overcoming resistance to conventional drugs in Ewing’s sarcoma and identification of molecular predictors of outcome.

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