Sustained Expression of the RON Receptor Tyrosine Kinase by

SustainedExpressionoftheRONReceptorTyrosineKinasebyPancreaticCancerStemCellsasaPotentialTargetingMoietyforAntibody-DirectedChemotherapeuticsSnehalS.Padhye,†,‡SunnyGuin,†,‡Hang-PingYao,§Yong-QingZhou,§RuiwenZhang,†,∥andMing-HaiWang*,†,‡†CancerBiologyCenterand‡DepartmentofBiomedicalSciences,SchoolofPharmacy,TexasTechUniversityHealthSciencesCenter,Amarillo,Texas79106,UnitedStates§NationalKeyLaboratoryforDiagnosisandTreatmentofInfectiousDiseasesandDepartmentofNeurosurgery,FirstAffiliatedHospital,ZhejiangUniversitySchoolofMedicine,Hangzhou,Zhejiang310003,P.R.China∥DepartmentofPharmaceuticalSciences,SchoolofPharmacy,TexasTechUniversityHealthSciencesCenter,Amarillo,Texas79106,UnitedStatesABSTRACT:Cancerstemcells(CSCs)contributetopancreaticcancertumorigenesisthroughtumorinitiation,drugresistance,andmetastasis.Currently,therapeuticstargetingpancreaticCSCsareunderintensiveinvestigation.ThisstudytestedanovelstrategythatutilizestheRONreceptorasadrugdeliverymoietyforincreasedtherapeuticactivityagainstpancreaticCSCs.CD24+CD44+ESA+triple-positivepancreaticCSCs(CSCs+24/44/ESA)wereobtainedfromspheroidsofpancreaticL3.6plcancercellsbysequentialmagneticcellsortingmethods.Thesecellsdisplayedasphericalgrowthpattern,expressedtheuniqueself-renewalmarkerBmi-1,redifferentiatedintoanepithelialphenotype,acquiredanepithelialtomesenchymalphenotype,andcausedtumorformationinanimalmodels.Amongseveralreceptortyrosinekinasesexamined,RONwashighlyexpressedandsustainedbyCSCs+24/44/ESA.Thisfeatureprovidedthecellu