ewing tumor as a model for systems biology andrei zinovyev service bioinformatique, institut curie
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Ewing tumor as a model for systems biologyEwing tumor as a model for systems biology
Andrei ZinovyevService Bioinformatique, Institut Curie
Systems Biology: statistical vs mechanistical models
perturbation
STATISTICALMODELING
perturbation
SYSTEMS BIOLOGYMODELING
EWING as a model system for cancer collaboration with Olivier Delattre UMR830 INSERM/Curie
EWS/FLI1 expressed
EWS/FLI1 silenced0
1
2
3
4
5
6
D10 D13 D17 D21
Nb
of
cell
s (X
106 )
“Simple” situation: one genetic event leads to cancer
shRNA
+DOX
-DOX
-DOX
Silencing and reactivation of EWS/FLI1 by inducible shRNA
Available Data collected for EWING
Microarrays:Microarrays:Experiments on EWS/FLI1 inhibition, time seriesPatients transcriptomes and CGHTranscriptome public data
CHiP-Chip:CHiP-Chip:High-density promoter arrays for EWS/FLI-1 TFTiling arrays for EWS/FLI-1 TF
miRNA:miRNA: Experiments on the inducible system
Data normalization and integration is essential
BioStat and BioIT groups BioStat and BioIT groups (Philippe Hup(Philippe Hupéé, Philippe La Rosa), Philippe La Rosa)
CELL PROLIFERATION
fb pathway
TGFpathway
IGF pathway
…
EWS/FLI1
Ewing network
APOPTOSIS
Datacollection
and generation
Biologicalnetwork
reconstruction
Networkmodeling
Predictionand
experimentdesign
How EWS/FLI-1 gene regulates proliferation and apoptosis?
Model-based analysis: switch-type response
-5
-4
-3
-2
-1
0
1
2
3
4
0 5 10 15 20
DAYS AFTER INHIBITION OF EWS/FLI-1
IG
FB
P3 e
xp
ressio
n
Experiment 1
Experiment2\
Response timeResponse speed
Switch score
First steps made
Mode analysis of time series of EWS/FLI1 inhibition (with use of PCA)Characterizing response time for every geneStatistical analysis of EWING patients data (ICA, clustering, classification)CHiP-chip analysis (several candidate targets are discovered)
Current researchReconstruction of genetic network around EWS/FLI1 using
promoter sequence analysismining literaturereverse network engineering from data
Analysis of microRNA time series
-5
-4
-3
-2
-1
0
1
2
3
4
0 5 10 15 20
DAYS AFTER INHIBITION OF EWS/FLI-1
IG
FB
P3 e
xp
ressio
nExperiment 1
Experiment2\
Pathway scoring by Gene Set Enrichment Analysis
Good switches Bad switches
TGF- pathway
SMAD targets
SMAD targets
-5
-4
-3
-2
-1
0
1
2
3
4
0 5 10 15
Days after EWS/FLI1 inactivation
LAMA4
TIMP1
COL1A2
LRRC17
IGFBP3
TGF-b and its receptor
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
2.5
0 5 10 15
Days after EWS/FLI1 inactivation
TGFBR2
TGFB2
EWING project participants
Bioinformatics Unit of Institut Curie Emmanuel Barillot Andrei ZinovyevEugene 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 athttp://bioinfo-out.curie.fr/projects/sitcon
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