| Summary: | Abstract Background: Tumorigenic transformationofhumanepithelialcellsinvitrohasbeendescribedexperimentallyas thepotentialresultofspontaneousimmortalization.Thisprocessischaracterizedbyaseriesofcell–statetransitions,in whichnormalepithelialcellsacquirefirstasenescentstatewhichislatersurpassedtoattainamesenchymalstem–like phenotypewithapotentiallytumorigenicbehavior.Inthispaperweaimtoprovideasystem–levelmechanistic explanationtotheemergenceofthesecelltypes,andtothetime–orderedtransitionpatternsthatarecommonto neoplasiasofepithelialorigin.Tothisend,wefirstintegratepublishedfunctionalandwell–curatedmoleculardataof thecomponentsandinteractionsthathavebeenfoundtobeinvolvedinsuchcellstatesandtransitionsintoa networkof41molecularcomponents.Wethenreducethisinitialnetworkbyremovingsimplemediators(i.e.,linear pathways),andformalizetheresultingregulatorycoreintologicalrulesthatgovernthedynamicsofeachofthe networkcomponentsasafunctionofthestatesofitsregulators. Results: ComputationaldynamicanalysisshowsthatourproposedGeneRegulatoryNetworkmodelrecoversexactly threeattractors,eachofthemdefinedbyaspecificgeneexpressionprofilethatcorrespondstotheepithelial, senescent,andmesenchymalstem–likecellularphenotypes,respectively.Weshowthatalthoughamesenchymal stem–likestatecanbeattainedevenunderunperturbedphysiologicalconditions,thelikelihoodofconvergingtothis stateisincreasedwhenpro–inflammatoryconditionsaresimulated,providingasystems–levelmechanistic explanationforthecarcinogenicroleofchronicinflammatoryconditionsobservedintheclinic.Wealsofoundthat theregulatorycoreyieldsanepigeneticlandscapethatrestrictstemporalpatternsofprogressionbetweenthesteady states,suchthatrecoveredpatternsresemblethetime–orderedtransitionsobservedduringthespontaneous immortalizationofepithelialcells,bothinvivoandinvitro. Conclusion: Ourstudystronglysuggeststhattheinvitrotumorigenictransformationofepithelialcells,which stronglycorrelateswiththepatternsobservedduringthepathologicalprogressionofepithelialcarcinogenesisinvivo, emergesfromunderlyingregulatorynetworksinvolvedinepithelialtrans–differentiationduringdevelopment. Keywords: Carcinomas,Generegulatorynetworks,Epigeneticlandscape,Booleanmodels,Phenotypicattractors
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