DevelopmentalCellReviewExosome-MediatedMetastasis:CommunicationfromaDistanceInbalWortzel,1,2ShaniDror,1,2CandiaM.Kenific,1,*andDavidLyden1,*1Children’sCancerandBloodFoundationLaboratories,DepartmentsofPediatrics,andCellandDevelopmentalBiology,DrukierInstituteforChildren’sHealth,MeyerCancerCenter,WeillCornellMedicine,NewYork,NY10021,USA2Theseauthorscontributedequally*Correspondence:cmk2009@med.cornell.edu(C.M.K.),dcl2001@med.cornell.edu(D.L.)https://doi.org/10.1016/j.devcel.2019.04.011Metastasis,acriticalphaseoftumorprogression,remainsaprimarychallengeintreatingcancerandamajorcauseofcancermortality.Cell-cellcommunicationviaextracellularvesicles(exosomesandmicrovesicles)betweenprimarytumorcellsandthemicroenvironmentofdistantorgansiscrucialforpre-metastaticniche(PMN)formationandmetastasis.Here,wereviewworkonthecontributionofexosomecargotocancerprogression,theroleofexosomesinPMNestablishment,andthefunctionofexosomesinorganotropicmetastasis.Wealsodescribetheclinicalutilityofexosomes.Introduction:Tumor-DerivedExosomesExosomesarenano-sizedvesicles(30–150nmdiameter)thataresecretedbymostcells.Theyareenclosedbyalipidbilayerandcarryvariousbiomolecules,includingproteins,glycans,lipids,metabolites,RNA,andDNA(Mathieuetal.,2019).Whenexosomesaretakenupbyothercells,thesecargoesaretrans-ferredandinfluencethephenotypeofrecipientcells.Assuch,exosomesareappreciatedasessentialmediatorsofcell-cellcommunication.Exosomebiogenesisoriginatesintheendocyticpathway(D’Souza-SchoreyandSchorey,2018;Mathieuetal.,2019;vanNieletal.,2018).Itbeginswithinvaginationofendosomallimitingmembranes,leadingtotheformationofintraluminalves-icles(ILVs)containedwithintheendosome.Thisresultingcompartment,termedamultivesicularbody(MVB),fuseswiththeplasmamembrane,culminatingintheextracellularreleaseofILVsasexosomes.Exosomeformationrequiresthecoordi-natedeffortsofseveralproteinnetworksinthecell.Amongtheseare(1)RabGTPaseproteins,whichcontrolendosomaltraf-ficking;(2)endosomalsortingcomplexesrequiredfortransport(ES...
