Squamouscellcarcinomas(SCCs)areamongthemostfre-quentsolidcancersinhumans1andrepresentamajorcauseofdeathworldwide.Theirincidenceissharplyrisingowingtoincreasedexposuretocarcinogens,suchasultravioletradiationrelatedtosunexposure,smoking,alcoholconsumptionorhumanpapillomavirus(HPV)infection1,2.SCCsareclassifiedaccordingtotheloca-tionwheretheyappear,beingfrequentlyfoundinskin,headandneck,oesophagus,lungandcervix2–6andmorerarelyinpancreas,thyroid,bladderandprostate7–10.Duringthepastdecades,greateffortshavebeenmadetoelucidatethecelloforiginofdifferentmalignancies11.Lineagetracingstudiesenabledtheidentificationofthecellularhierarchiesandlineagesegregationthatmediatehomeostasisandrepairofthedifferenttissuesfromwhichcancerarises12(FiG.1).Manycancersarisefromtissuesmaintainedbythepresenceofstemcellsandprogenitorsthatself-renewanddifferentiateintothedifferentcelllineagesthatcomposethesetissues.Dependingontheturnover,differentiatedcellsandprogenitorsusuallypres-entashorterlifespan,whereasstemcellsresidelongterm,sometimesthroughoutthelifeoftheanimals.Upontissuedamage,thecellularhierarchythatgovernsepithelialtissuehomeostasiscanbealtered,andmorecommittedprogenitorsandevendifferentiatedcellscanacquirestemcellpotentialandcontributetotissuerepair13.Withoncogenichits,bothstemcellsandprogenitorscanserveasthecellsoforiginincancer(Box1).Thenatureofthecellsatthecanceroriginhasalsobeenproposedtodeterminethedifferentiationcharac-teristicsandaggressivenessoftumours.Tumoursarisingfromprogenitorsmayshowlineage-restricteddifferen-tiation,whereastumoursarisingfromstemcellscouldpresentmultilineagedifferentiationpotential.However,multipotentdifferentiationofatumourcouldalsoresultfromplasticityoftumourcellsinducedbytheironco-genicmutationsorbytheirmicroenvironmentorbyneighbouringcells.InthisReview,wediscussrecentstudiesthatdefinethecelloforiginofcutaneous,headandneck,oesopha-gealandlungSCCs,whichrepresentthemostcommonSCCs.Wefirstdescribethearchitectureandcellularhierarchypresentinthedifferent...
