Re-engineeringthePancreasTumorMicroenvironment:A"RegenerativeProgram"HackedGerardI.Evan1,NasunHah2,TrevorD.Littlewood1,NicoleM.Sodir1,TaniaCampos1,MichaelDownes2,andRonaldM.Evans2,3AbstractThe"hallmarks"ofpancreaticductaladenocarcinoma(PDAC)includeproliferative,invasive,andmetastatictumorcellsandanassociateddensedesmoplasiacomprisedoffibroblasts,pancreaticstellatecells,extracellularmatrix,andimmunecells.Theoncogenicallyactivatedpancreaticepi-theliumanditsassociatedstromaareobligatorilyinterde-pendent,withtheresultinginflammatoryandimmunosup-pressivemicroenvironmentcontributinggreatlytotheevo-lutionandmaintenanceofPDAC.Thepeculiarpancreas-specifictumorphenotypeisaconsequenceofoncogeneshackingtheresidentpancreasregenerativeprogram,atis-sue-specificrepairmechanismregulatedbydiscretesuperenhancernetworks.Definedasgenomicregionscontainingclustersofmultipleenhancers,superenhancersplaypivotalrolesincell/tissuespecification,identity,andmaintenance.Hence,interferingwithsuchsuperenhancer–drivenrepairnetworksshouldexertadisproportionatelydisruptiveeffectontumorversusnormalpancreatictissue.Noveldrugsthatdirectlyorindirectlyinhibitprocessesregulatingepigeneticstatusandintegrity,includingthosedrivenbyhistonedea-cetylases,histonemethyltransferaseandhydroxylases,DNAmethyltransferases,variousmetabolicenzymes,andbromo-domainandextraterminalmotifproteins,haveshownthefeasibilityofdisruptingsuperenhancer–dependenttran-scriptionintreatingmultipletumortypes,includingPDAC.Theideathatpancreaticadenocarcinomasrelyonembeddedsuperenhancertranscriptionalmechanismssuggestsavul-nerabilitythatcanbepotentiallytargetedasnoveltherapiesforthisintractabledisease.ClinCancerRes;23(7);1647–55.�2017AACR.SeeallarticlesinthisCCRFocussection,''PancreaticCancer:ChallengeandInspiration.''IntroductionPancreaticcancerisadevastatingneoplasticdiseasethatisbecomingincreasinglycommonandisprojectedtosurpassbreastcancerasacauseofdeathinthenextfewyears.IntheUnitedStatesalone,53,670peoplearediagnosedwithpan-creasc...
