ContentslistsavailableatScienceDirectSeminarsinCancerBiologyjournalhomepage:www.elsevier.com/locate/semcancerReviewMetabolismandepigeneticsofpancreaticcancerstemcellsM.PerusinaLanfrancaa,J.K.Thompsona,F.Bednara,b,C.Halbrookb,c,C.Lyssiotisb,c,B.Levia,T.L.Frankela,b,⁎aDepartmentofSurgery,UniversityofMichigan,AnnArbor,MI,UnitedStatesbRogelCancerCenter,UniversityofMichigan,AnnArbor,MI,UnitedStatescMolecularandIntegrativePhysiology,UniversityofMichiganMedicalSchool,AnnArbor,MI,UnitedStatesARTICLEINFOKeywords:PancreaticcancerCancerstemcellsEpithelial-to-mesenchymaltransitionStemnessAcinar-ductal-metaplasiaMetabolismEpigeneticsABSTRACTPancreaticCancer(PDA)isanaggressivemalignancycharacterizedbyearlyspreadandahighmortality.Currentstudiessuggestthatasubpopulationofcellsexistwithintumors,cancerstemcell(CSC),whicharecapableofself-renewalandgiverisetouniqueprogenywhichformthemajorneoplasticcellularcomponentoftumors.WhileCSCsconstituteasmallcellularsubpopulationwithinthetumor,theirresistancetochemotherapyandradiationmakethemanimportanttherapeutictargetforeradication.Alongwithdistinctivephenotypicprop-erties,CSCspossessauniquemetabolicplasticityallowingthemtorapidlyrespondandadapttoenvironmentalchanges.ThesecellsandtheirprogenyalsodisplayasignificantlyalteredepigeneticstatewithdistinctivepatternsofDNAmethylation.Severalmechanismsofcross-talkbetweenepigeneticandmetabolicpathwaysinPDAexistwhichultimatelycontributetotheobservedcellularplasticityandenhancedtumorigenesis.Inthisreviewwediscussvariousexamplesofthismetabolic-epigeneticinterplayandhowitmayconstituteanewavenuefortherapyspecificallytargetingCSCsinPDA.1.IntroductionPancreaticCancer(PDA)isanaggressivemalignancy,usuallydi-agnosedatadvancedstagesandwithadismallylow5yearsurvivalrateoflessthan9%[1].Earlydiseasespreadandlocalinvasioncombinedwiththehighincidenceofchemoresistanceandlackofeffectiveim-munotherapy,makesPDAthe3rdleadingcauseofcancer-relateddeathintheUnitedStates[2,3].Cancerstemcells(CSC)areundifferentiatedquiescentc...
