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Ewing tumor as a model for systems biology

Ewing tumor as a model for systems biology. Andrei Zinovyev Service Bioinformatique, Institut Curie. Systems Biology: statistical vs mechanistical models. perturbation. SYSTEMS BIOLOGY MODELING. perturbation. STATISTICAL MODELING. Primary objectives. Breast cancer. Bladder cancer.

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Ewing tumor as a model for systems biology

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  1. Ewing tumor as a model for systems biology Andrei Zinovyev Service Bioinformatique, Institut Curie

  2. Systems Biology: statisticalvs mechanistical models perturbation SYSTEMS BIOLOGY MODELING perturbation STATISTICAL MODELING

  3. Primary objectives Breast cancer Bladder cancer Pediatric cancers … others

  4. EWING tumor Poorly differentiated cells of unknown origin Adolescent patients Age

  5. EWS/FLI1 expressed shRNA +DOX -DOX EWS/FLI1 silenced 6 5 -DOX 4 Nb of cells (X106) 3 2 1 0 D10 D13 D17 D21 EWING as a model system for cancer collaboration with Olivier Delattre UMR830 INSERM/Curie “Simple” situation: one genetic event leads to cancer Silencing and reactivation of EWS/FLI1 by inducible shRNA

  6. Available Data collected for EWING Microarrays: Experiments on EWS/FLI1 inhibition, time series Patients transcriptomes and CGH Transcriptome public data CHiP-Chip: High-density promoter arrays for EWS/FLI-1 TF Tiling arrays for EWS/FLI-1 TF miRNA: Experiments on the inducible system Data normalization and integration is essential BioStat and BioIT groups (Philippe Hupé, Philippe La Rosa)

  7. IGF pathway … EWS/FLI1 CELL PROLIFERATION direct targets secondary targets TGFb pathway APOPTOSIS Nfkb pathway Ewing network How EWS/FLI-1 gene regulates proliferation and apoptosis? Data collection and generation Network modeling Biological network reconstruction Prediction and experiment design

  8. Response time Response speed Model-based analysis: switch-type response Switch score

  9. First steps made Mode analysis of time series of EWS/FLI1 inhibition (with use of PCA) Characterizing response time for every gene Statistical analysis of EWING patients data (ICA, clustering, classification) CHiP-chip analysis (several candidate targets are discovered) Current research Reconstruction of genetic network around EWS/FLI1 using promoter sequence analysis mining literature reverse network engineering from data Analysis of microRNA time series

  10. SMAD targets Good switches Bad switches Pathway scoring by Gene Set Enrichment Analysis TGF-b pathway

  11. EWING project participants Bioinformatics Unit of Institut Curie Emmanuel Barillot Andrei Zinovyev Eugene Novikov Gautier Stoll Philippe Hupé "Genetics and biology of pediatric tumours" Olivier Delattre Franck Tirode Karine Laud Noelle Guillon EWING projectis funded by ANR Systems Biology program (2007-2009):project SITCON (Modeling SIgnal Transduction caused by a Chimeric ONcogene) Further details about SITCON at http://bioinfo-out.curie.fr/projects/sitcon

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