1 ProjectAbstract:Althoughthenumberofpeopledevelopingbreastcancer(BC)eachyearhasremainedthe 2 same,5-yearsurvivalratesforlatestagediseasearestillanabysmal17-26%.However,onepositiveindicator 3 ofsurvivalishowwellthepatient?simmunesystemisabletorecognizethetumorandattackit,usingimmune 4 cells like tumor-associated macrophages (TAMs). Basal-like, triple negative BC (TNBC) is a uniquely deadly 5 typeofBCandaccountsforabout20%ofBCcases.TNBCdoesnotgrowbecauseofhormoneandgrowth 6 factors,butinsteadfrequentlyactivatesotherpro-growthsignalsliketheexpressionofsecretedWNTproteins 7 thatactasmessengerstonearbycells.Inaddition,TNBCismorelikelytomanipulatetheimmunesysteminto 8 a tumor-promoting mechanism instead of a tumor-fighting one. This is accomplished by inducing TAMs to 9 programintoatumor-promotingM2state,whichhelpscreateanenvironmentfortumorstothrivebypromoting 10 bloodvesselgrowth,insteadofatumor-fightingM1state.WehaveidentifiedtheDEKproteinasakeydriverof 11 BCgrowthanddiseaseprogression.DEKishighlyexpressed?meaningtoomuchproteinismadecompared 12 to normal cells - in about 60% of all breast cancers, especially TNBC. DEK is over-expressed in all types of 13 cancerstudiedsofar,meaningthatunderstandinghowDEKfunctionstopromotecancergrowthanddisease 14 progressioncouldhaveafar-reachingimpactinunderstandingcancerbiology.Wehavepreviouslyusedcultured 15 cellstodiscoverthatDEKpromotestheproliferationofcancercellsbyincreasingtheexpressionofseveralWNT 16 genesthatthengetsecretedtoactonneighboringcells,buthavenotyetinvestigatedthisinanimalmodels. 17 Interestingly,ourpreliminarydatasuggestthattheWNTproteinsproducedbyDEK-expressingcancercellsmay 18 signal to TAMs to enter an M2-like state to further promote tumor growth. We hypothesize that DEK over- 19 expression in BC promotes tumor formation via elevated WNT expression, which acts both on neighboring 20 epithelialcellsandonmacrophages.Wewillusethree-dimensionalcellcultureofhumancells,patientsamples, 21 andnewmousemodelsofBCtotestthishypothesis.
In Aim1, wewilluseanewDEKover-expressionmodel 22 in the mammary epithelium of mice to Determine when and how DEK promotes tumor growth. We will also 23 determinethenecessityforcontinuedDEKexpressiontomaintaintumorgrowth,whichwillinformthefeasibility 24 ofcreatingDEK-targetingtherapiesinthefuture.
Aim2 willinvestigatehowimportantWNTproteinsareforthe 25 abilityofDEKtopromotetumorgrowthandprogression.Finally,Aim3willexaminehowDEKandWNTproteins 26 worktogethertoinduceTAMstoenterthetumor-promotingM2state.Thisworkwillbethefirsttobothinvestigate 27 theconsequencesofDEKover-expressioninananimalmodelandthefirsttoexaminetheabilityofWNTproteins 28 tosignaltotheimmunesystemduringcancerdevelopmentandprogression.UnderstandinghowDEKpromotes 29 tumorgrowth,includingdownstreameffectsonTAMs,willbetterinformtherapeuticdecisionsthatmaximize 30 thecollaborationbetweenchemotherapyandtheanti-?tumorimmuneresponse.
The DEK oncogene is over-expressed in ~60% of breast cancers as well as in all other solid tumors tested to date; however, the mechanisms by which it promotes tumor formation and growth are very poorly understood. We have recently identified that one potential mechanism of DEK-induced oncogenic phenotypes is the upregulation of Wnt expression and downstream pathway activation, which is a common occurrence in triple negative breast cancer. Importantly, we are the first to investigate how Wnt proteins may induce an M2-like polarization of tumor associated macrophages in order to convert the immune system into a tumor-promoting role rather than a tumor-fighting one. Understanding how DEK promotes tumorigenesis, including the potential relationship between Wnt signaling and anti-tumor immune responses from TAMs, will better inform treatment decisions and potentially maximize the therapeutic effect of combining immunotherapies and chemotherapy.
