AWnt-producingnichedrivesproliferativepotentialandprogressioninlungadenocarcinomaTuomasTammela1,FranciscoJ.Sanchez-Rivera1,NaniyeMalliCetinbas1,KatherineWu1,NikhilS.Joshi1,KatjaHelenius1,YoonaPark1,RoxanaAzimi1,NatanyaR.Kerper1,R.AlexanderWesselhoeft1,XinGu1,LeahSchmidt1,MiltonCornwall-Brady1,ÖmerH.Yilmaz1,WenXue1,5,PekkaKatajisto3,4,ArjunBhutkar1,andTylerJacks1,21DavidH.KochInstituteforIntegrativeCancerResearch,MassachusettsInstituteofTechnology,Cambridge,MA02142,USA2HowardHughesMedicalInstitute,MassachusettsInstituteofTechnology,Cambridge,MA02139,USA3InstituteofBiotechnology,UniversityofHelsinki,00014Helsinki,Finland4DepartmentofBiosciencesandNutrition,KarolinskaInstitutet,14183,Stockholm,Sweden5RNATherapeuticsInstitute,PrograminMolecularMedicine,andDepartmentofMolecular,CellandCancerBiology,UniversityofMassachusettsMedicalSchool,Worcester,MA01605,USAAbstractTheheterogeneityofcellularstatesincancerhasbeenlinkedtodrugresistance,cancerprogressionandpresenceofcancercellswithpropertiesofnormaltissuestemcells1,2.SecretedWntsignalsmaintainstemcellsinvariousepithelialtissues,includinginlungdevelopmentandregeneration3–5.Herewereportthatmurineandhumanlungadenocarcinomasdisplayhierarchicalfeatureswithtwodistinctsubpopulations,onewithhighWntsignalingactivityandanotherforminganichethatprovidestheWntligand.TheWntrespondercellsshowedincreasedtumourpropagationability,suggestingthattheyhavefeaturesofnormaltissuestemcells.GeneticperturbationofWntproductionorsignalingsuppressedtumourprogression.Smallmoleculeinhibitorstargetingessentialpost-translationalmodificationofWntreducedtumourgrowthanddramaticallydecreasedproliferativepotentialofthelungcancercells,leadingtoimprovedsurvivaloftumour-bearingmice.Theseresultsindicatethatstrategiesfordisruptingpathwaysthatmaintainstem-likeandnichecellphenotypescantranslateintoeffectiveanti-cancertherapies.Usersmayview,print,copy,anddownloadtextanddata-minethecontentinsuchdocuments,forthepurposesofacademicresearch,subjectalwaystothefullConditi...
