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

Primary objectives

Breast cancer

Bladder cancer

Pediatric cancers

… others

EWING tumor

Poorly differentiated cellsof unknown origin

Age

Adolescent patients

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

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-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

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-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