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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA218072-02
Application #
9645045
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Hildesheim, Jeffrey
Project Start
2018-02-08
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229