Abstract

Lungcanceristhoughttodevelopinastepwisefashiongivingustheopportunitytointervenebeforeitbecomes invasive.Anovelapproachtocurepatientsoflungcanceristhereforetodevelopatargetedchemoprevention strategytopreventtheformationoflungpremalignantlesionsinthefirstplace.Mylabstudiesairwaybasalstem cells(ABSCs)andthesignalingpathwaysinvolvedintheirrepairandregenerationafterinjury.Ourstudiesled ustotheconclusionthatpremalignancyrepresentsastateofexcessiveself-renewalofABSCswithablockin differentiation and we identified several mechanisms involved in stepwise progression to Squamous Lung Cancer.OnesuchmechanisminvolvesproliferationofABSCsviatheWnt-?-cateninpathwayandinparticular wefoundthatonlyoneofthedifferentialphosphorylationsites,thetyrosineY489residueofthe?-cateninprotein, allowed nuclear localization of ?-catenin with concomitant TCF/LEF activation for proliferation. We found that phosphorylation of other classically described ?-catenin phosphorylation sites only resulted in membranous localizationof?-catenin.Thephosphorylationof?-cateninatY489(p-?-cateninY489)isnotpresentinnormal airwayABSCsandisturnedononlybrieflyduringnormalrepairafterinjury,butitpersistsinpremalignantlesion ABSCsandinasubsetofcellsinSquamousLungCancer(SLC). Our goal is to understand the mechanisms that drive phosphorylation of ?-catenin at Y489 and discover compoundstopreventthisprocess.Thiswillallowustopreventtheexcessiveproliferationofpremalignancy anddevelopanovelchemopreventionstrategyforSLC.Wewillachievethisgoalwiththefollowingaims:
SpecificAim1 :Tounderstandtheroleofp-?-cateninY489inproliferationofABSCs,premalignantlesionsand lungcancers.Wehypothesizethatp-?-cateninY489isacommonmechanismforproliferationinallhistologic subtypesoflungcancer.
Specific Aim 2 : To identify the kinase/s responsible for phosphorylation of ?-cateninY489 site in ABSCs. We hypothesize that there are specific kinase/s that phosphorylate ?-catenin at the Y489 site which drives proliferationofABSCstoformpremalignantlesions.
Specific Aim 3 : To identify compounds that prevent p-?-cateninY489. We will perform a targeted screen of compoundsthatpreventTCF/LEFactivationinABSCsalongwithatoxicityscreen.Thiswillallowustoidentify compoundsthatinhibitproliferationbutarenottoxictoABSCs.Leadcompoundsfromthisprimaryscreenwill betakentoasecondaryscreenwithimmunofluorescenceforp-?-cateninY489. Ourhighlyaccomplishedresearchteam,theoutstandingenvironmentatUCLAandtheimportantbiologythatis being addressed in this proposal all provide a high likelihood that this NCI Provocative Question 1 will be answeredfortargetingpremalignancyinNon-SmallCellLungCancerandleadtothedevelopmentofatargeted chemopreventionstrategyforLungCancerthatwillsavemillionsoflives.

Public Health Relevance

Wehavefoundamechanismforhowprecancerouslesionsinthelungdevelopintolungcancer. Thegoalofthisproposalistofurtherourunderstandingofthismechanismanduseadrugscreen tofinddrugsthatpreventprecancerouslesionsandthereforelungcancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA208303-02
Application #
9330823
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Szabo, Eva
Project Start
2016-08-15
Project End
2021-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Wilkinson, Dan C; Mellody, Michael; Meneses, Luisa K et al. (2018) Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling. Curr Protoc Stem Cell Biol 46:e56