.Complexityincancerstemcellsandtumorevolution:towardsprecisionmedicineCaterinaA.M.LaPorta∗a,b,StefanoZapperia,c,d,e,faCenterforComplexityandBiosystems,UniversityofMilan,viaCeloria16,20133Milano,Italy.bDepartmentofBiosciences,UniversityofMilan,viaCeloria26,20133Milano,ItalycDepartmentofPhysics,UniversityofMilan,viaCeloria16,20133Milano,Italy.dInstituteforScientificInterchangeFoundation,ViaAlassio11/C,10126Torino,ItalyeDepartmentofAppliedPhysics,AaltoUniversity,P.O.Box11100,FIN-00076Aalto,Espoo,FinlandfCNR-ConsiglioNazionaledelleRicerche,ICMATE,ViaR.Cozzi53,20125Milano,Italy∗Correspondingauthor:caterina.laporta@unimi.itAbstractInthisreview,wediscussrecentadvancesontheplasticityofcancerstemcellsandhighlighttheirrelevancetounderstandthemetastaticprocessandtoguidetherapeuticinterventions.Re-centresultssuggestthatthestricthierarchicalstructureofcancercellpopulationsadvocatedbythecancerstemcellmodelmustbereconsideredsincethedepletionofcancerstemcellsleadstheothertumorcellstoswitchbackintothecancerstemcellphenotype.Thisplasticityhasimportantimplicationsformetastasissincemigratingcellsdonotneedtobecancerstemcellsinordertoseedametastasis.Wealsodiscusstheimportantroleoftheimmunesystemandthemicroenvironmentinmodulatingphenotypicswitchingandsuggestpossibleavenuestoexploitourunderstandingofthisprocesstodevelopaneffectivestrategyforprecisionmedicine.Keywords:,cancerstemcells,phenotypicswitching,metastasis,precisionmedicineDotumorsgrowstochasticallyorhierarchically?Twomainmodelshavebeenusedinthepasttodescribetumordevelopment:inthestochas-ticclonalevolutionmodel[1],eachcellscanbetumorigenicandsustaintumorgrowth,whileaccordingtothecancerstemcell(CSC)theory[2],thetumorisorganizedhierarchicallywithasubpopulationofcellssustainingthegrowth.Therelevanceofeitheroneortheothertheoryhasarelevancefortherapeuticstrategies[3,4].Whereasthestochasticmodelsuggeststhatthebesttherapeuticstrategyistokillallcancercellstargetingsomecommonfactors,accordingtotheCSCtheorythebeststrategyshouldbetoprima...
