atlas of cancer signalling network and navicell · 2017-10-26 · “computational systems biology...
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“ComputationalSystemsBiologyofCancer”U900InstitutCurie/INSERM/Ecole desMinesParisTech,Paris,France
InnaKuperstein
ATLASOFCANCERSIGNALLINGNETWORKANDNAVICELL
SYSTEMSBIOLOGYRESOURCESFORSRUDYINGCANCERBIOLOGY
CANCER:ACOMPLEXSYSTEM
AtlasofCancerSignalling NetworkResourceofknowledgeonmolecularmechanismsandanalyticaltool
Atlas of Cancer Signaling Networks
http://acsn.curie.fr
MapandMap
PresentPast
Atlas of Cancer Signaling Networks
AtlasofCancerSignalling NetworksResourceofknowledgeonmolecularmechanismsandanalyticaltool
AgilentprojectGARUDAproject
AtlasofCancerSignalling Network:navigatingcancerbiologywithGoogleMapsKupersteinI,BonnetE, NguyenHA,CohenD,Grieco L,Viara E,Fourquet S,CalzoneL,RussoC,Kondratova M,Dutreix M,Barillot EandZinovyev A.Oncogenesis, 2015
http://acsn.curie.fr
VisualsyntaxSystemsBiologyGraphicalNotation(SBGN)
Biologicalmoleculesandinteractionsrepresentation
Standardsandtoolsforsignalling networksconstruction
Tool:CellDesignerDiagrameditorforsignalling networksrepresentation
SystemsBiologyMarkupLanguage(SBML)Computationalrepresentationofbiochemicalprocesses
K1*X0
Standardsandtoolsforsignalling networksconstruction
ü Cancer-relatedü Manuallycuratedü Comprehensiveandup-to-dateü Interconnectedü Browsable andzoomable
AtlasofCancerSignalling Network:navigatingcancerbiologywithGoogleMapsKupersteinI,BonnetE, NguyenHA,CohenD,Grieco L,Viara E,Fourquet S,CalzoneL,RussoC,Kondratova M,Dutreix M,Barillot EandZinovyev A.Oncogenesis, 2015
Applicablefor:ü Dataintegrationü Network−baseddataanalysisü Modelingsyntheticinteractionsü Predictiondrugresistancemechanisms
ü 5mapsofbiologicalprocessesü 52functionalmodulesü 4826reactionsü 2371proteinsü 5979chemicalspeciesü 2822references
http://acsn.curie.fr
Atlas of Cancer Signaling Networks
Ongoing:signalingmapsinconstructionØ ImmuneresponseandtumormicroenvironmentØ RegulatedcelldeathØ TelomeremaintenanceØ AngiogenesisØ CentrosomeregulationØ CellpolarityØ DNAreplication
Intercellularnetwork Intracellularnetwork
AtlasofCancerSignalling NetworkResourceofknowledgeonmolecularmechanismsandanalyticaltool
Atlas of Cancer Signaling Networks
Regulatedcelldeathmap:manymodestodie
https://navicell.curie.fr/maps/pcd/master [email protected]
http://acsn.curie.fr
Initiation(reversible)STRESSRESPONSEANTIOXIDANTRESPONSEDNADAMAGERESPONSEERSTRESSSTARVATION-AUTOPHAGY
LIGAND-RECEPTORDEATHRECEPTORPATHWAYSTRAILRESPONSEFASRESPONSETNFRESPONSE
DEPENDENCERECEPTORMETABOLISMCELLMETABOLISMFATTYACIDBIOSYNTHESISGLUCOSEMETABOLISMGLUTAMINEMETABOLISMPENTOSEPHOSPHATEPATHWAYPORPHYRINMETABOLISM
MITOCHONDRIALMETABOLISMOXIDATIVEPHOSPHORYLATIONANDTCACYCLEMITOCHONDRIALGENES
Signaling (rewirable)APOPTOSISNECROPTOSISFERROPTOSISPARTHANATOSPYROPTOSIS
Execution(irreversible)MOMPREGULATIONMITOCHONDRIALPERMEABILITYTRANSITIONCASPASESRCDGENES
Layers- 3Metamodules- 15Modules- 14
Mapcontent
Chemicalspecies- 2657Proteins- 1008Reactions- 2020Articles- 738
Networkofmodules
Annotatedcelltypes
ü Macrophagesü MDSCü Neutrophilsü Dendriticcellsü Neutrophilsü Mastcells
Pro-tumor Anti-tumorpolarization
Metamapofinnateimmuneresponseincancer
Chemicalspecies- 1476Proteins- 583Reactions- 1085Articles- 812
TUMORRECOGNITION
IMMUNESTIMULATION
TUMORKILLING
TUMORGROWTH
IMMUNESUPPRESSION
RECRUITMENTINHIBITIONOFTUMORRECOGNITION
CORESIGNALING
Annotatedarticles
Layers- 3Metamodules - 4Modules- 20
Mapcontent
Googlemap
NaviCell:aweb-basedenvironmentfornavigation,curation andmaintenanceoflargemolecularinteractionmapsKupersteinI,CohenDP,Pook S,Viara E,CalzoneL,Barillot E,Zinovyev A. BMCSystemsBiology,2013
Dataintegration
http://navicell.curie.fr
üGoogleengine(navigation,search,markers,calloutwindow)ü Semanticzoomingü Entityannotationpost
üDataintegrationandvisualization(online)ü Entityneighborhoodstudyü Functionalanalysis(enrichmentofmodules)
Blog
Semanticzoom
NaviCell WebServiceforNetwork-basedDataVisualizationBonnetE,Viara E,KupersteinI,CalzoneL,CohenDPA,Barillot E,Zinovyev A.NucleicAcidResearch,2015
NaviCell = Map(GoogleMapsengine)+Blog(WordPress)+ToolBox
Awebtoolfornavigation,curationanddataanalysisinthecontextofsignalling networks
Towardsgeographicinformationsystemformolecularbiology
DatatypesContinuousdata:mRNAexpressionmicroRNAexpressionProteinexpressionCopynumber
Discretedata:Post-translationalmodificationsMutationdataGenelistCopynumber
NaviCom:Pythonpackageandwebinterfacetocreateinteractivemolecularnetworkportraitsusingmulti-levelomicsdataDorelM,Viara E,Barillot E,Zinovyev AandKuperstein I.DATABASE,Biocuration issue,2017 [email protected]
http://navicell.curie.fr
NaviCell WebServiceforNetwork-basedDataVisualizationBonnetE,Viara E,KupersteinI,CalzoneL,CohenDPA,Barillot E,Zinovyev A.NucleicAcidResearch,2015
http://[email protected]
Data$type$ Visualiza.on$mode$ Data$display$ Units$
mRNA%expression% Map%staining% Level%
Gene%copy%number% Heat%map% Count%
Muta<on%data% Glyph%1% Frequency%
Methyla<on%data% Glyph%2% Intensity%
miRNA%expression% Glyph%3% Level%%
Protein%expression%% Glyph%4% Level%
Up
Down
MolecularportraitofBreastInvasiveCarcinomavisualizedonCellcyclemap
expression-mapstainingcopynumber-heatmapmutations-bluetrianglemethylation-pinkdiamondproteomics-yellowcircle
Visualizationsettings
NETWORKSINPRE-CLINICALRESEARCH
Cisplatin DNAcross-links
DNAdamageaccumulation Tumorcell
death
!!!Resistance DNArepairmachinery
TreatmentapproachesincancerGenotoxic drugs
ApproachExploitspecificitiesintumorcellswhichdisplayabnormalexpressionorfunctionofonegenefromsyntheticlethalpair.Targetingsyntheticlethalpartnerallowsselectivekillingoftumorcells.
BRCA/PARPsyntheticlethalpair
TreatmentapproachesincancerTargeteddrugs:syntheticlethalityparadigm
!!!Resistance DNArepairmachinery
SyntheticlethalitybetweentwogenesExtremecaseofnegativegeneticinteractions
Dobzhansky Genetics(1946)
Syntheticlethality:mutationsinnumberofgenesproducingaphenotypethatissignificantlydifferentfromeachmutation'sindividualeffects
GeneA GeneB Cellfate
Syntheticgeneticinteractions
Negativegeneticinteraction:aggravating effectPositivegeneticinteraction:ameliorating effect
Syntheticlethalgeneset=interventiongeneset
Questions:-Whatexplainsresistancetogenotoxic treatmentincancer?-Canwerestoresensitivitytotreatment?-Howtoidentifypatient-specifictargetstorestoresensitivitytogenotoxic treatment?
Interventiongenesetsforcancerpatientsresistanttogenotoxic treatment
Signalling networks forinterventionstrategydesignStructuralanalysis
IntactDNAlocus
RepairedDNA
Doublestrandbreak
Drug1
Drug2
Drug n
PointsofPARPinvolvementinDNArepairnetwork
DNArepairnetwork
OCSANA:anintegrativepathwayanalysisto revealinterventiongenesets
PrioritizingthelistofmasterregulatorsIdentifyingpointsoffragilityinthenetworkIdentifyingsyntheticlethalcombinations
Target Elementary Pathways
Elementary Nodes
Computation Time
Total Number of MinHitSets
MinHitSetsSize 1
MinHitSets Size 2
MinHitSets Size 3
MinHitSets Size 4
MinHitSets Size 5
Comments
KPNA2 2300 198 5.51 252 0 0 108 42 102
MAD2L1 2214 131 7.43 74 9 5 12 7 42
CFL1 (Cofilin)
15 71 7.40 38336 6 0 160 4848 33322
CDC20 198 126 2.04 74 8 5 12 7 42
XPO1 529 171 2.40 112 0 6 30 32 44 Antiapoptotic
CyclinB1 1476 121 1.21 74 1 5 12 7 42 Downregulated by BRCA1 and p53. Upregulated by USF-1 (which is upregulated by BRCA2)
MAD2L1&BUB1B
246 119 0.24 86 21 0 12 7 42 Study of Combinations
Conf.information
Minimalcutsets
OCSANA:optimalcombinationsofinterventionsfromnetworkanalysisVera-Licona P,BonnetE,Barillot E,Zinovyev A.Bioinformatics,2013
Survival to DT01 (%/NT)
Surv
ival
to O
lapa
rib (%
/NT)
60 80 100 1200
105060708090
100110120
MDAMB436
HCC1937BC227
HCC38HeLa BRCA1
HeLa BRCA2
BC173
MDAMB468
HCC1143
BT20 MDAMB231
MCF7
HCC1187
HCC70
HeLa CTL
184B5
MCF10AMCF12A
Trypan blue staining andcounting 10dafter treatment
Survival of Triple negative Breast cancer cell lines to Dbait or Olaparib
Tumorheterogeneity:explainingresistancetotargetedtreatment
DNArepairinhibitorsDbait andOlaparib
DrugDrivenSyntheticLethality:bypassingtumorcellgeneticswithacombinationofDbait andPARPinhibitorsJdey W,ThierryS,Russo C,Devun F,AlAbo M,Noguiez-Hellin P,Sun JS,Barillot E,Zinovyev A,KupersteinI,Pommier Y,Dutreix M.ClinicalCancer Research,2016
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
p−value (a.u.)
Prec
enta
ge o
f ove
rlapp
ing
gene
s (%
)
●
●
●
●
●
●
●
0.000 0.002 0.004 0.006 0.008
0.00
00.
001
0.00
20.
003
p−value (a.u.)
Prec
enta
ge o
f ove
rlapp
ing
gene
s (%
)
!
Gene
Correlation with Survival
to DT01 ACSN
modules Gene
Correlation with Survival to Olaparib
ACSN modules
PPP2R5C 0.8725275 4 MYH6 0.8406593 2 RAP1GDS1 0.8637363 2 CSK 0.83296704 4 PTEN 0.83516484 4 PFKFB3 0.83296704 3 CCNA1 0.8186813 3 MAPK6 0.8065934 3 NOTCH1 0.8186813 2 UBE2Q2 0.8021978 3 TEAD1 0.7758242 3 FECH 0.789011 2 PIK3CA 0.7692308 3 TP53 0.7846154 9 STK11 0.7582418 2 COPS2 0.7802198 2 ROCK1 0.75384617 3 CTNND2 0.7802198 2 HRAS 0.73626375 5 GNB5 0.7714286 3 DEF6 0.73186815 2 TAB2 0.7692308 5 CAPN2 0.72747254 4 NFE2L1 0.7582418 3 CUL1 0.72307694 5 PRKCH 0.75274724 3 ARHGEF1 0.70357144 2 PPP2R5E 0.74945056 3 BCL2L11 -0.72747254 6 UBE2Z 0.74945056 3 GADD45B -0.73186815 2 FKBP8 0.74505496 2 FZD5 -0.73186815 2 PIAS1 0.73626375 3 NGEF -0.73186815 2 ITGB4 0.72747254 2 GNG7 -0.73626375 3 GCLC 0.72747254 2 NR4A1 -0.75384617 2 RPS6KA5 0.7214286 3 MYCN -0.7714286 2 ATP5J -0.74505496 2 FYN -0.7802198 4 ARHGAP31 -0.75384617 2 GRK6 -0.7978022 2 CDH2 -0.7692308 5 PPP2R5D -0.8131868 4 PRKAG3 -0.7802198 4 NDUFA6 -0.8153846 2 LAMA4 -0.789011 2 HSPA1A -0.81978023 2 PRDX2 -0.8021978 2 FLT1 -0.82417583 4 ACTA1 -0.8131868 6 COL1A1 -0.82417583 2 GADD45G -0.8131868 2 AKT3 -0.8296703 4 PRKCB -0.82857144 4 ROR2 -0.85494506 2 TCF3 -0.83296704 5 COL6A2 -0.88461536 2
UniquegenesrobustlycorrelatedwithresistancetoDbait (left)orOlaparib (right)inTNBCcelllines.ThelistsarerestrictedtogenesenrichedatleastintwoACSNmodules.
Red - positivecorrelation, green- negativecorrelationwithsurvivaltodrugs.Thevaluesarecorrelationcoefficients(Spearmanr;Pvalue<0.004)betweengeneexpressionandsurvivaltoDbait orOlaparib
UniquegenesrobustlycorrelatedwithresistancetoDbait orOlaparib
intriplenegativebreastcancercelllines
DrugDrivenSyntheticLethality:bypassingtumorcellgeneticswithacombinationofDbait andPARPinhibitorsJdey W,ThierryS,Russo C,Devun F,AlAbo M,Noguiez-Hellin P,Sun JS,Barillot E,Zinovyev A,KupersteinI,Pommier Y,Dutreix M.ClinicalCancer Research,2016
ACSNmodulesenrichment:differentregulationbyDbait orOlaparibintriplenegativebreastcancercelllines
CoverageofACSNmodulesbygenesrobustlycorrelatedwithresistancetoDbait
CoverageofACSNmodulesbygenesroubastly correlatedwithresistancetoOlaparib
Correlationwithsurvivaltotreatment:Red– positiveGreen - negative
DrugDrivenSyntheticLethality:bypassingtumorcellgeneticswithacombinationofDbait andPARPinhibitorsJdey W,ThierryS,Russo C,Devun F,AlAbo M,Noguiez-Hellin P,Sun JS,Barillot E,Zinovyev A,KupersteinI,Pommier Y,Dutreix M.ClinicalCancer Research,2016
Dbait resistant Olaparib resistant
mRNAexpression
Up
DownMutationsCopynumber loss
gain
MolecularportraitsofresistancetoDbait orOlaparib:multi-omics dataintegrationintriplenegativebreastcancercelllines
DrugDrivenSyntheticLethality:bypassingtumorcellgeneticswithacombinationofDbait andPARPinhibitorsJdey W,ThierryS,Russo C,Devun F,AlAbo M,Noguiez-Hellin P,Sun JS,Barillot E,Zinovyev A,KupersteinI,Pommier Y,Dutreix M.ClinicalCancer Research,2016
Mechanismsofaction:trapDNArepairmachinerywithcombinationofinhibitorsDbait andOlaparib
Olaparib Dbait
SurvivalofbreastcancercelllinestocombinedtreatmentwithDbail andOlaparib
SurvivalofcontrolcelllinestocombinedtreatmentwithDbail andOlaparib
Olaparib
DT014.8µM+Olaparib
Exp.Add.DT014.8µM+Olaparib
Olaparib([µM](
0(20(40(60(80(
100(120(
0( 0.1( 1(
MDAMB231(
0(20(40(60(80(
100(120(
0( 0.1( 1(
BC173(
0"20"40"60"80"100"120"
0" 0.1" 1"
MCF10A'
0"20"40"60"80"
100"120"
0" 0.1" 1"
MCF12A'
Olaparib"[µM]"""""
"""""""""""""""""""""Living"cells"(%
/NT)"
DrugDrivenSyntheticLethality:bypassingtumorcellgeneticswithacombinationofDbait andPARPinhibitorsJdey W,ThierryS,Russo C,Devun F,AlAbo M,Noguiez-Hellin P,Sun JS,Barillot E,Zinovyev A,KupersteinI,Pommier Y,Dutreix M.ClinicalCancer Research,2016
Livingcells(%
/NT)
Macrophage
TumormicroenvironmentCell-typespecificmaps
Dendritic cell
Cancer-associated fibroblast
Naturalkiller
Multi-cellular system
Networkofmodules
Annotatedcelltypes
ü Macrophagesü MDSCü Neutrophilsü Dendriticcellsü Neutrophilsü MastcellsPro-tumor Anti-tumorpolarization
Metamapofinnateimmuneresponseincancer
Chemicalspecies- 1476Proteins- 583Reactions- 1085Articles- 812
TUMORRECOGNITION
IMMUNESTIMULATION
TUMORKILLING
TUMORGROWTH
IMMUNESUPPRESSION
RECRUITMENTINHIBITIONOFTUMORRECOGNITION
CORESIGNALINGLayers- 3Metamodules - 4Modules- 20
Mapcontent
Mixtureofindependentsources:cocktailpartyproblem
å=
×»m
i
gFi ssampleFiActivityassampleggeneExpression
1),(),(
Factor 1
Gene 1 Gene 2 Gene 3 Gene n…
21Fa 3
1FanFa 1
11Fa
Factor 2 Factor m…
12Fa 2
2Fa32Fa
nFa 2
1Fma
2Fma3Fma
nFma m << n
• Performsmatrixfactorizationbyminimizingmutualinformationbetweenfactors
• Stabilityanalysis,determiningtheoptimalnumberofcomponents(Kairov etal,2017)
• Toolboxofmethodsforinterpretingtheresultingmetagenes andmetasamples
• GraphicaluserinterfaceimplementedinJavaPossibilitytovisualizeICAcomponentsontopofdiseasemapsinNaviCell
IndependentComponentAnalysis(ICA)deconvolutionofomicsprofiles
https://github.com/LabBandSB/BIODICA
Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypesBiton A,Bernard-Pierrot I,LouY,Krucker C,Chapeaublanc E,Rubio-PérezC,López-Bigas N,Kamoun A,Neuzillet Y,Gestraud P,Grieco L,Rebouissou S,deReyniès A,Benhamou S,Lebret T,SouthgateJ,Barillot E,AlloryY,Zinovyev A,Radvanyi F.CellReports,2014
Meta-analysisofindependentfactorsinsolidcancers
6671 tumor samples (20000-30000 genes in each sample), 22 datasets, 9 cancer types
Metaanalysisofmultipleindependentdatasets
Transcriptome data set 1
Transcriptome data set 2
Transcriptome data set 3
metagene 1metagene 2
metagene 3 metagene Imetagene II
metagene III metagene Ametagene B
metagene C
Hospital1 Hospital2 Hospital3
1
I
A
2 C
II
B
Metagene correlationgraph Visualisation inNaviCell
ROMA:calculatingpathwayactivitiesfromomicsdata
• Quantifiesgenesetoverdispersion• Basedonsimplelinearmodelofgene
regulation• Assignsascoretoeachsample
(weightedmean)• Candefinepositiveandnegative
pathwayregulatorsaspriorknowledge• Thescorescanbevisualizedontopof
thediseasemapsinNaviCell• JavaandRimplementation
http://sysbio.curie.fr/softwareROMA:RepresentationandQuantificationofModuleActivityfromTargetExpressionDataMartignetti L,CalzoneL,BonnetE,Barillot E,Zinovyev A.FrontiersinGenetics,2016
Class2:Cytokinesand
chemokinesproduction
up-regulation
down-regulation
updown
Cancerassociatedfibroblastsheterogeneityinmetastaticmelanomasamples
Class1:Growthfactorsproduction
Class3:Matrixregulation
CLASS1
CLASS2
CLASS3
CLASS4
Singlecell transcriptome datafrom:Dissecting themulticellular ecosystem ofmetastatic melanoma bysingle-cell RNA-seqTirosh Ietal,Science2016
IdentificationoffourCAFclassesusingtranscriptomicdata
IC1_minus
IC1_plus
ICAmethod:BitonAetal,Independentcomponentanalysis uncovers thelandscape ofthebladder tumor transcriptomeandreveals insightsinto luminal andbasalsubtypes.Cell Rep 9(4):1235-45,2014
CancerassociatedfibroblastcellmapVisualizationofmoduleactivitydifferencebetweenthreeclasses
PC1
PC2
NaturalkillercellmapVisualizationofmoduleactivitydifferencebetweenNK1andNK2classes
MetamapofinnateimmuneresponseincancerVisualizationofmoduleactivitydifferencebetweenNK1andNK2classes
Innateimmunecellpolarizationandheterogeneityinmetastaticmelanomasamples
Naturalkillercells
up-regulation
down-regulation
Singlecell transcriptome datafrom:Dissecting themulticellular ecosystem ofmetastatic melanoma bysingle-cell RNA-seqTirosh Ietal,Science2016
IdentificationoftwoNKclassesusingtranscriptomicdata
CLASS1
CLASS2
ICAmethod:BitonAetal,Independentcomponentanalysisuncovers thelandscape ofthebladder tumortranscriptome andreveals insightsinto luminal andbasalsubtypes.Cell Rep 9(4):1235-45,2014
Innateimmunecellpolarizationandheterogeneityinmetastaticmelanomasamples
Macrophages
up-regulation
down-regulation
PC1
PC2
MacrophagecellmapVisualizationofmoduleactivitydifferencebetweenMK1andMK2classes
MetamapofinnateimmuneresponseincancerVisualizationofmoduleactivitydifferencebetweenMK1andMK2groups
IdentificationoftwoMKclassesusingtranscriptomicdata
CLASS1
CLASS2
Singlecell transcriptome datafrom:Dissecting themulticellular ecosystem ofmetastatic melanoma bysingle-cell RNA-seqTirosh Ietal,Science2016
ICAmethod:BitonAetal,Independentcomponentanalysis uncovers thelandscape ofthebladder tumor transcriptomeandreveals insightsinto luminal andbasalsubtypes.Cell Rep 9(4):1235-45,2014
Colon cancer genetics
?
From Fearon&Vogelstein, Cell 1990
Coloncancerisassociatedwith:MutationsinAPC gene(b-catenin/WNT pathway)MutationsinRASandp53 genesLessfrequentmutationsinmanyotherpathways(Notch,MLH,PTEN,SMAD,etc.
Experimentalsystem:mousewithapossibilityofconditionalmutationsingut(villin-CreERT2tamoxifen-dependentintestine-specificrecombination)
Question:Canwefindacombinationofmutationsinpathwaysleadingtorapidmetastasis?
Predictionofinvasivephenotypeinmicemodelofcoloncancer
Fromsignalingnetworkanalysistohypothesisandtoexperimentalvalidation
LineagetracinginmouseintestinerevealsEMTandmetastasisinvivofollowingNotchactivationandp53deletionChanrion M*,KupersteinI*,Barrière C,ElMarjou F,CohenD,Vignjevic D,Stimmer L,Paul-Gilloteaux P,Bièche I,DosReisTavaresS,Boccia GF,Cacheux W,Meseure D,Fre S,Martignetti L,Legoix-NéP,GirardE,Fetler L,Barillot E,Louvard D,Zinovyev A andRobine S.NatureCommunications,2014NetworkbiologyelucidatesmetastaticcoloncancermechanismsKupersteinI,Robine SandZinovyev A.CellCycle,2015
Epithelial-Mesenchymal Transition(EMT)anecessaryconditiontoappearanceofmetastases
From Friedl and Alexander, Cell, 2011
LineagetracinginmouseintestinerevealsEMTandmetastasisinvivofollowingNotchactivationandp53deletionChanrion M*,KupersteinI*,Barrière C,ElMarjou F,CohenD,Vignjevic D,Stimmer L,Paul-Gilloteaux P,Bièche I,DosReisTavaresS,Boccia GF,Cacheux W,Meseure D,Fre S,Martignetti L,Legoix-NéP,GirardE,Fetler L,Barillot E,Louvard D,Zinovyev A andRobine S.NatureCommunications,2014NetworkbiologyelucidatesmetastaticcoloncancermechanismsKupersteinI,Robine SandZinovyev A.CellCycle,2015
Visualizingcentralplayers
Pathanalysis
Modelreduction
Comprehensivenetworkofepithelialtomesenchymal transition(EMT)regulation Hubregulators
StructuralanalysisofEMTregulationnetwork
LineagetracinginmouseintestinerevealsEMTandmetastasisinvivofollowingNotchactivationandp53deletionChanrion M*,KupersteinI*,Barrière C,ElMarjou F,CohenD,Vignjevic D,Stimmer L,Paul-Gilloteaux P,Bièche I,DosReisTavaresS,Boccia GF,Cacheux W,Meseure D,Fre S,Martignetti L,Legoix-NéP,GirardE,Fetler L,Barillot E,Louvard D,Zinovyev A andRobine S.NatureCommunications,2014NetworkbiologyelucidatesmetastaticcoloncancermechanismsKupersteinI,Robine SandZinovyev A.CellCycle,2015
Syntheticinteractionbetweenp53andoverexpressionofNotch(NICD)leadstoEMT
NICD
NICD is up p53 is down
LineagetracinginmouseintestinerevealsEMTandmetastasisinvivofollowingNotchactivationandp53deletionChanrion M*,KupersteinI*,Barrière C,ElMarjou F,CohenD,Vignjevic D,Stimmer L,Paul-Gilloteaux P,Bièche I,DosReisTavaresS,Boccia GF,Cacheux W,Meseure D,Fre S,Martignetti L,Legoix-NéP,GirardE,Fetler L,Barillot E,Louvard D,Zinovyev A andRobine S.NatureCommunications,2014NetworkbiologyelucidatesmetastaticcoloncancermechanismsKupersteinI,Robine SandZinovyev A.CellCycle,2015
EMT
NORMAL
MicemodelofcoloncancerwithmetastasesindistantorgansNICD++/p53-- mice
• Allmice developed adenocarcinoma 15months postinduction• Compared tosinglemutants,showdrastic decrease insurvival• 50%developed peritoneal carcinomatosis,23.3%infiltrated lymph nodes,10%liver metastases
• Patternsofdistantmetastases resembles primary tumours• GFPstaining confirms theintestinalorigin ofthecancercells from primary andsecondary organs
LineagetracinginmouseintestinerevealsEMTandmetastasisinvivofollowingNotchactivationandp53deletionChanrion M*,KupersteinI*,Barrière C,ElMarjou F,CohenD,Vignjevic D,Stimmer L,Paul-Gilloteaux P,Bièche I,DosReisTavaresS,Boccia GF,Cacheux W,Meseure D,Fre S,Martignetti L,Legoix-NéP,GirardE,Fetler L,Barillot E,Louvard D,Zinovyev A andRobine S.NatureCommunications,2014NetworkbiologyelucidatesmetastaticcoloncancermechanismsKupersteinI,Robine SandZinovyev A.CellCycle,2015
Invasivecoloncancermodelrelevantforhumandisease
Transcription factor
significant differential expression
module activity
ExpressionofNotch,P53andWnt downstream targets inTCGAcolontumours
LineagetracinginmouseintestinerevealsEMTandmetastasisinvivofollowingNotchactivationandp53deletionChanrion M*,KupersteinI*,Barrière C,ElMarjou F,CohenD,Vignjevic D,Stimmer L,Paul-Gilloteaux P,Bièche I,DosReisTavaresS,Boccia GF,Cacheux W,Meseure D,Fre S,Martignetti L,Legoix-NéP,GirardE,Fetler L,Barillot E,Louvard D,Zinovyev A andRobine S.NatureCommunications,2014NetworkbiologyelucidatesmetastaticcoloncancermechanismsKupersteinI,Robine SandZinovyev A.CellCycle,2015
Conclusions:toolsACSN is a resource of cancer signalling knowledgeComprehensive map of molecular interactions in cancer based on the latest scientific literature
NaviCell: Interactive web-based environment for navigation data integration and visualizationTool for navigation and curationGoogle Maps engine and semantic zooming mechanismAssociated with blog system for discussion forum around the ACSN contentVisualization of omics data
OCSANA: tool for network analysisSuggest intervention gene setsRationalize drug combination
Independent component analysis: deconvolution of complex dataMeta data analysisCancer heterogeneity
ROMA: calculating pathway activities from omics dataDeregulated functional modulesMolecular portraits of cancer
FromaBiologicalHypothesistotheConstructionofaMathematicalModelCohenD,KupersteinI,BarillotE,ZinovyevA,CalzoneL.Methodsinmolecularbiology,2013BiologicalnetworkmodellingandprecisionmedicineinoncologyCalzoneL,KupersteinI,CohenD,GriecoL,BonnetE,ServantN,HupeP,ZinovyevA,BarillotE.Bull.Cancer,2014Theshortestpathisnottheoneyouknow:applicationofbiologicalnetworkresourcesinprecisiononcologyresearchKupersteinI,GriecoL,CohenD,ThieffryD,ZinovyevA,BarillotA.Mutagenesis,2015Network-basedapproachesfordrugresponsepredictionandtargetedtherapydevelopmentincancerDorelM,BarillotE,ZinovyevAandKupersteinI.BiochemBiophysResCommun,2015
Conclusions:applications
APPLICATION 3: Tumor heterogeneity: find and characterize cells sub-populationCell type-specific maps together with meta-map allow to study heterogeneity of cell populations intumor microenvironment.There are multiple sub-classes in the population of TME cells demonstrating subtle differences in the setof implicated functional modules that dictate the heterogeneity.
FromaBiologicalHypothesistotheConstructionofaMathematicalModelCohenD,KupersteinI,BarillotE,ZinovyevA,CalzoneL.Methodsinmolecularbiology,2013BiologicalnetworkmodellingandprecisionmedicineinoncologyCalzoneL,KupersteinI,CohenD,GriecoL,BonnetE,ServantN,HupeP,ZinovyevA,BarillotE.Bull.Cancer,2014Theshortestpathisnottheoneyouknow:applicationofbiologicalnetworkresourcesinprecisiononcologyresearchKupersteinI,GriecoL,CohenD,ThieffryD,ZinovyevA,BarillotA.Mutagenesis,2015Network-basedapproachesfordrugresponsepredictionandtargetedtherapydevelopmentincancerDorelM,BarillotE,ZinovyevAandKupersteinI.BiochemBiophysResCommun,2015
APPLICATION1:Resistancetogenotoxicdrugs:InterventiongenesetsRetrieveprinciplesofsignalingcoordinationandsyntheticinteractionsFindsignalingnetworkfragilitiesinthediseaseSuggestinterventiongenesets
APPLICATION 2:SynergybetweentargeteddrugsInterpretomicsdatafromcelllineswithdifferentsensitivitytotargeteddrugsinthecontextofsignalingnetworkRetrievederegulatedfunctionalmodulesSuggestsynergybetweendrugs
APPLICATION4:InvasivephenotypeincoloncancerinmicemodelPredictionofnon-intuitivecombinationofsyntheticallyinteractinggenesFormulatinghypothesisonmolecularmechanismandexperimentalvalidationofprediction
ComputationalSystemsBiologyofCancerGroupInstitutCurie,Paris,FranceBarillot EmmanuelBiton AnneBonnetEricCalzoneLaurenceCohenDavidCzerwinska UrszulaDorelMathurinFourquet SimonGrieco LucaKondratova MariaMonraz GLCristobalNguyễn Hiển AnhPicat LeoSompairac NicolasPook StuartRavelJean-MarieRussoChristopheVera-Licona PaulaViara EricZinovyev Andrei
AcknowledgementsInstitutdeRecherches Servier,Croissy sur Seine,FranceGordonTuckerFranciscoCruzalegui
SystemsBiologyInstitut,Tokyo,JapanHiroakiKitanoSamik GhoshYukiko Matsuoka
KEGGteam,KyotoUniversity,Kyoto,JapanMinoruKanehisa
UniversityofCalifornia,Davis,CA,USWolf-DietrichHeyer
AgilentTechnologies,Inc.,SantaClara,CA,USNigelSkinnerNortonKitagawaAntoni WandyczCarolinaLivi
InstitutCurie,Paris,FranceDanielLouvardSylvieRobineCharrion MaiaCelineBaldeyronThierryDuboisFatimaMechta-GrigoriouYannKiefferVassiliSomelisPhilippeChavrierMarc-HenriSternTatyana PopovaChristopheLeTourneauMaudKamal
InstitutCurie,Orsay,FranceSimonSauleLauraDucielMarieDutreixJdey WaelMounira Amor-GuéretJanetHall
InstitutGustave Roussy,Villejuif,FranceMuratSaparbaevPilippo RoselliPatriciaKannouche
EcoleNormaleSupérieureDépartementdeBiologie,Paris,FranceDenisThieffryWassim Abou-Jaoudé
CentredeRecherchedesCordeliers,Paris,FranceGuidoKroemerLorenzoGalluzzi