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

Systems Biology: statistical vs mechanistical models perturbation STATISTICAL MODELING perturbation SYSTEMS BIOLOGY MODELING

Primary objectives Breast cancer Bladder cancer Pediatric cancers … others

EWING tumor Poorly differentiated cells of unknown origin Age Adolescent p atients

EWING as a model system for cancer collaboration with Olivier Delattre UMR830 INSERM/Curie EWS/FLI1 expressed EWS/FLI1 silenced D10D13D17D21 Nb of cells (X10 6 ) “Simple” situation: one genetic event leads to cancer shRNA +DOX -DOX Silencing and reactivation of EWS/FLI1 by inducible shRNA

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)

CELL PROLIFERATION  f  b pathway TGF  pathway IGF pathway … EWS/FLI1 Ewing network APOPTOSIS Data collection and generation Biological network reconstruction Network modeling Prediction and experiment design How EWS/FLI-1 gene regulates proliferation and apoptosis?

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

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

Pathway scoring by Gene Set Enrichment Analysis Good switchesBad switches TGF-  pathway SMAD targets

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 project is funded by ANR Systems Biology program ( ): project SITCON (Modeling SIgnal Transduction caused by a Chimeric ONcogene) Further details about SITCON at