CancerCellReviewNotchSignalingintheTumorMicroenvironmentOlivierMeurette1,*andPatrickMehlen11Apoptosis,CancerandDevelopmentLaboratory-EquipeLabellise´e‘LaLigue’,LabExDEVweCAN,CentredeRechercheenCance´rologiedeLyon,INSERMU1052-CNRSUMR5286,Universite´deLyon,CentreLe´onBe´rard,69008Lyon,France*Correspondence:olivier.meurette@lyon.unicancer.frhttps://doi.org/10.1016/j.ccell.2018.07.009TheNotchsignalingpathwayregulatesmanyaspectsofcancerbiology.Mostattentionhasbeengiventoitsroleinthetransformedcell.However,itisnowclearthatcancerprogressionandmetastasisdependonthebidirectionalinteractionsbetweencancercellsandtheirenvironment,formingthetumormicroenvironment(TME).Theseinteractionsaremediatedandconstantlyevolvethroughparacrineandjuxtacrinesignaling.Inthisreview,wediscusshowNotchsignalingtakesanimportantpartinregulatingthecrosstalkbetweenthedifferentcompartmentsoftheTME.WealsoaddresstheconsequencesoftheNotch-TMEinvolvementfromatherapeuticperspective.IntroductionThetumorisanorgan-likestructurethatresultsfromtheco-evo-lutionofmalignantcellsandtheirdirectenvironment.Thetumormicroenvironment(TME)encompassesallthestructuresthatarerecruitedtothisorgan:vascularvessels,immuneinfiltrates,fi-broblasts,andtheextracellularmatrix.Tumorprogression,resis-tancetotherapy,invasion,andmetastasisareemergentproper-tiesofthebidirectionalinteractionsbetweenthecancercellsandtheTME(HanahanandCoussens,2012;QuailandJoyce,2013).Understandingtheco-evolutionofthecancercellsandtheirphysicalandcellularenvironmentiscrucialforthedevelopmentofnewefficienttherapies.Thecrosstalkbetweenthecancercellsandtheirenvironmentinvolvereciprocaljuxtacrineandparacrinesignalingusingmanydifferentpathways.Amongthem,theNotchsignalingpathwayisanimportantpathwaythatisrecognizedasamajoractorbothinthecancercellsandineachofthecomponentsoftheTME.TheroleoftheNotchsignalingpathwayincancercellseitheractinginanoncogenicoratumor-suppressivemannerhasbeenextensivelyreviewed(Asteretal.,2017;NowellandRadtke,2017;Ntziachristosetal.,20...
