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InvestigatingtheroleofcellcyclecontrolbyFbxo7inthe developmentofT-cellmalignancies LeadInvestigator: Co-Investigator: HeikeLaman DepartmentofPathology http://www.path.cam.ac.uk/directory/heike-laman SuzanneTurner DepartmentofPathology http://www.path.cam.ac.uk/directory/suzanne-turner ThisPhDpositioninthePaediatricCancerProgrammeprovidesauniqueopportunityforahighly motivatedindividualtoconductresearchwithinestablishedlabsinvestigatingmechanismsofcell cyclecontrolincancer.Thestudentwillgainskillsandexpertiseintheareasofcellbiologyand biochemistry,andinthefieldsofcellcycleregulation,Tcellbiology,andinvivomodels. ProjectDescription ThederegulationoftheG1/Sphasetransitionoccursregularlyinmultiplecancersubtypes,including Tcellmalignancies(1).Thiscanhappenasaresultofdirectmutations,includinginactivationof tumoursuppressorgenes,liketheINK4familymembersofcyclindependentkinase(Cdk)inhibitors, CDKN2aandCDKN2b,theretinoblastomageneRB1,and/ortheoverexpressionoftheprotooncogenicsubunitsoftheG1phasekinase,Cdk6andcyclinsD2andD3.Interestingly,cyclinD3and Cdk6arealsoabsolutelyrequiredfortumoursarisingfromtheaberrantactivationofother oncogenicsignallingpathways,makingthefidelityandfunctionofthispathwaycriticalforcancers, evenifso-called‘driver’mutationsdonotoccurinitscorecomponents.Forexample,micelacking Cdk6areresistanttothymiclymphomacausedbyconstitutivelyactiveAktsignalling,whereasmice lackingcyclinD3arealsofullyresistanttotheaggressivethymiclymphomaresultingfromactivated Notchsignalling(2;3).TheG1cellcyclepathwayanditscoremachinerythereforerepresent importantpotentialtherapeutictargets,andunderstandinghowthedisruptionofthiscircuitryaids tumourdevelopmentandhowthiscanbepreventedisimportant. OurlaboratoryhasdiscoveredtheF-boxprotein,Fbxo7,hasnon-SCF-dependentactivity,actingasa cellcycleregulatorthatdirectlystabilisesp27andCdk6,enhancingitsactivationbyD-typecyclins (4).Fbxo7hasoncogenicactivityasitsover-expressioninp53nullhaematopoieticstemand progenitorcells(HSPCs)causesT-celllymphomainvivo(5).Morerecently,wehavefoundthatthe lossofFbxo7expressionrevealedithasopposingrolesoncellproliferationwithintheTcelllineage atdifferentdevelopmentalstages.Paradoxically,itpromotesproliferationofthymocyteswithinthe thymus,butrestrainedproliferationofactivatedTcellsintheperiphery.Thiscontradictoryactivity ofFbxo7indicatesthattheG1phasecircuitryduringTcelldevelopmentisdifferentiallyregulated fromthatofmatureTcells.ThissetsupthepossibilitythatFbxo7mayberequiredforT-cell malignanciesderivingfromimmaturethymocytes,butmayactasatumoursuppressorgenein malignanciesderivingfromperipheralTcells.ThisPhDprojectsetsouttotestthisideadirectlyusing culturedcelllinesofanumberofimmature(e.g.Tlymphoblasticlymphoma/leukaemia)andmature Tcellmalignancies(e.g.AnaplasticLargeCellLymphoma;ALCL)todeterminewhetherFbxo7 regulatesthecellcycledifferentiallyinthesedifferenttumourtypesandwhetheritcanpromoteor suppressoncogenicitydependingonthestageofTcellmaturation,usinginducibleexpressionand knock-outsystems.Dependingonourfindings,wewilluseaNucleophosmin-AnaplasticLymphoma Kinase(NPM-ALK)-drivenmousemodelofTcellmalignancythatcanbeengineeredtoariseinthe thymusortheperiphery(6)totestthetumour-suppressiveortumour-promotingeffectofFbxo7on tumoursarisingindifferentnicheenvironments.Thestudentwillgainskillsandexpertiseinthe areasofcellbiologyandbiochemistry,andinthefieldsofcellcycleregulation,Tcellbiology,andin vivomodels. References (1) HanahanD,WeinbergRA.Hallmarksofcancer:thenextgeneration.Cell2011;144(5):646-674. (2) HuMG,DeshpandeA,EnosM,MaoD,HindsEA,HuGFetal.Arequirementforcyclin-dependent kinase6inthymocytedevelopmentandtumorigenesis.CancerRes2009;69(3):810-818. (3) SicinskaE,AifantisI,LeCamL,SwatW,BorowskiC,YuQetal.RequirementforcyclinD3in lymphocytedevelopmentandTcellleukemias.CancerCell2003;4(6):451-461. (4) NelsonDE,RandleSJ,LamanH.Beyondubiquitination:theatypicalfunctionsofFbxo7andother F-boxproteins.OpenBiol2013;3(10):130131. (5) LomonosovM,MezianeeK,YeH,NelsonDE,RandleSJ,LamanH.ExpressionofFbxo7in haematopoieticprogenitorcellscooperateswithp53losstopromotelymphomagenesis.PLoS One2011;6(6):e21165. (6) MalcolmTI,VillareseP,FairbairnCJ,LamantL,TrinquandA,HookCEetal.Anaplasticlargecell lymphomaarisesinthymocytesandrequirestransientTCRexpressionforthymicegress.Nat Commun2016;7:10087. Applications Toapplyforthisstudentshiphttp://www.cambridgecancercentre.org.uk/studentships ForgeneralenquiriespleasecontactTinaThorn [email protected] Forfurtherinformationorquestionsrelatingtothisprojectpleasecontact HeikeLaman [email protected]
