Overthepastseveraldecades,cancerhaslargelybeentreatedasadiseaseofaberrantproliferationandsurvival,andthetherapiesmostcommonlyusedtoday—radia-tionandchemotherapy—mainlytargettheseproper-ties.Despitethesuccessesofcytotoxictherapies,whichincludecuresachievedinchildhoodacutelymphoblasticleukaemia(ALL)1andlymphoma2,itisalsoclearthatwearereachingthelimitsofhoweffectivetheseapproachescanbe,atleastintheircurrentform.Thus,ithasbecomeimportanttoexamineaspectsofoncogenesisbeyondaberrantsurvivalandproliferation.Onecriticalaspectofthechangesthatoccurasbenignlesionstransitiontomalignantonesisthepro-gressiveacquisitionoftheundifferentiatedstate.Benignlesionsareoftenmoredifferentiated,whilemalignanciesaremoreundifferentiated,suggestingareversalofthedifferentiationsignalsputinplaceduringdevelopment.Asmanyofthesignalsthatdrivetheundifferentiatedstatearealsokeytoconferringastemcellfate,itisper-hapsnotsurprisingthatmanycancersshowanacutedependenceonthesesignalstomaintaintheirmoreaggressivestate.Inaddition,stemcellsignalsarealsointegrallylinkedtocancerinitiation,propagationandtherapyresistance.Whiledrivermutationsarekeytoinitiatingoncogene-sis,thecellsinwhichthesemutationsoccurareofequalimportance;thus,mutationsthatcannottransformdif-ferentiatedcellscantransformundifferentiatedones3–6,suggestingthatthestemorprogenitorcellstateprovidesamorepermissivecontextfortransformation.Evenaftercancerestablishment,perpetuationofastemcellstateinsomecellscreatescancerstemcells(CSCs),‘drivercells’thatarepreferentiallyaggressiveandposeahighriskoftherapyresistanceanddiseaserelapse7.Thus,under-standingandtargetingthesignalscriticaltosustainingthesecellsareessentialtoimprovingoutcomes.Here,wefocusonhowregulationofstemcellfatecannotonlyinfluencecancerinitiationbutalsoserveasadrivereventfordiseaseprogression,therapyresistanceandmetastaticgrowth.StemcellstatesincancerinitiationTranscriptionalcontextandthecelloforigin.Keystud-ieshaveshownthatsubsetsofcellswithstemandpro-genitorcharacteristicsinnormalti...
