Cellularsenescenceisatumorsuppressivecellgrowtharresttriggeredbyinducerssuchas activationofoncogenesandchemotherapeutics.However,senescentcellsareviableandmaypromote tumorprogressionandtherapyrelapsethroughsecretionoffactorssuchascytokines,chemokinesand growthfactors,termedthesenescence-associatedsecretoryphenotype(SASP).Thus,itwouldbeideal toenhancesenescence-associatedgrowtharrestwhilelimitingSASPbecausethismayleadtoadurable therapeuticoutcome.Notably,itremainstobedeterminedwhethersilencingofproliferationgenesand upregulationofSASPgenesarecoupledatthemolecularlevel.Thus,theoverallgoalofthisproposalis toinvestigatethemechanismthatcoordinatesthesilencingofproliferationgenesandtheupregulationof SASPgenesduringsenescenceanditsimplicationsincancerandresponsetotherapy.HMGB2isa chromatinarchitectureproteinthatbindstoDNAwithoutsequencespecificity.Ourpreliminarydata suggestthatHMGB2orchestratesgeneexpressionreprogrammingduringsenescencebyactingasa molecularswitch.Specifically,lossofHMGB2fromgenomiclociofproliferationgenescontributestotheir silencing.Incontrast,HMGB2?sredistributiontoSASPgeneslocipromotestheirexpression.Consistent withitsroleinsenescence,HMGB2isoftenupregulatedinepithelialovariancancer(EOC)andits expressioncorrelateswithEOCprogression.Further,expressionofHMGB2positivelycorrelateswithits targetproliferationgenesinEOCs.Basedonthesefindings,ourcentralhypothesisisthatHMGB2 orchestratesgeneexpressionreprogrammingtoregulatetheswitchfromproliferationtosenescence. WealsohypothesizethatHMGB2contributestoEOCbysuppressingsenescenceandpromotes platinum-basedtherapyrelapsebydrivingSASP.Accordingly,twospecificaimsareproposed:
Aim1 : ToelucidatethemolecularmechanismbywhichHMGB2regulatessenescence;?andAim2:To determinetheroleofHMGB2inEOCandtherapyrelapse.Theproposedstudiesarehighlynovel becausethisisthefirststudytoexploreanovelmolecularmechanismthatorchestratesthesilencingof proliferation-promotinggenesandtheupregulationofSASPgenesduringsenescence.Thus,ourstudies areparadigmshiftingintheirpotentialtoelucidatethemolecularbasisofgeneexpression reprogrammingduringsenescence.Theresearchproposedisofhighimpactbecausetheywilllaythe criticalfoundationforultimatelydevelopingnovelstrategiesthatharnessthetumor-suppressivebenefitof senescence,whilelimitingthedetrimentalaspectsofSASPtoultimatelyachievedurabletherapy outcome.Therefore,thecurrentstudywillnotonlyprovidecriticalmechanisticinsightsintogene expressionreprogrammingduringsenescence,butwillalsohavefar-reachingimplicationsforthe developmentofsenescence-basedtherapeuticstrategies.

Public Health Relevance

Theproposedresearchisrelevanttopublichealthbecauseitwillrevealacriticalmolecular switchthatcontrolscellularsenescence,animportanttumorsuppressionmechanism.Thesemolecular insightsmayprovidescientificrationaletoultimatelydevelopnovelstrategieswithadurabletherapeutic outcomeforcancersincludingovariancancer,themostlethalgynecologicalmalignancyintheUnited States.Therefore,theproposedresearchisrelevanttothepartoftheNIH?smissionthatpertainsto developingfundamentalknowledgethatwillreducetheburdenofhumanillness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA160331-06A1
Application #
9390303
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
2012-06-01
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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