ExosomesFacilitateTherapeuticTargetingofOncogenicKrasinPancreaticCancerSushrutKamerkar1,ValerieS.LeBleu1,HikaruSugimoto1,SujuanYang1,CarolinaF.Ruivo2,SoniaA.Melo1,2,J.JackLee3,andRaghuKalluri1,*1DepartmentofCancerBiology,MetastasisResearchCenter,UniversityofTexasMDAndersonCancerCenter,Houston,TX770052InstitutodeInvestigaçãoeInovaçãoemSaúde,UniversidadedoPorto,Portugal(I3S),4200Porto,Portugal;InstituteofPathologyandMolecularImmunologyoftheUniversityofPorto(IPATIMUP),4200Porto,Portugal3DepartmentofBiostatistics,UniversityofTexasMDAndersonCancerCenter,Houston,TX77005SummaryThemutantformoftheGTPaseKRASisakeydriverofpancreaticcancerbutremainsachallengingtherapeutictarget.Exosomes,extracellularvesiclesgeneratedbyallcells,arenaturallypresentintheblood.Herewedemonstratethatenhancedretentionofexosomesincirculation,comparedtoliposomes,isduetoCD47mediatedprotectionofexosomesfromphagocytosisbymonocytesandmacrophages.Exosomesderivedfromnormalfibroblast-likeUsersmayview,print,copy,anddownloadtextanddata-minethecontentinsuchdocuments,forthepurposesofacademicresearch,subjectalwaystothefullConditionsofuse:http://www.nature.com/authors/editorial_policies/license.html#terms*Correspondence:RaghuKalluri,MD,PhD,rkalluri@mdanderson.org.AuthorcontributionsRKconceptuallydesignedthestrategyforthisstudy,providedintellectualinputandcontributedtothewritingofthemanuscript.HSandVSLinjectedmiceorthotopicallywithtumorcells.HSperformednecropsyanalysesandquantitationoftheexosomesinpancreastissuesections.VSLprovidedintellectualinput,extractedtheRNAandquantifiedthesiRNAloadinginexosomesbyqPCRanalyses,stainedtissuesforKras,helpedwiththemonitoringofinvivoexperiments,designedtheexperimentalstrategy,preparedfiguresandwrotethemanuscript.SKandSYpreparedexosomes(culturedcellsforexosomescollectionandpreparationbyultracentrifugation),generatediExosomes(performedelectroporationandwashstepsinvolvedinthegenerationofiExosomesandNanosight™measurements),andtreatedmicewithiExosomes.SYalsoperformedanindependen...
