Abstract

Inecosystemmodeling,theAlleeeffectdescribesacorrelationbetweenpopulationsize(numberofmembers) andmeanfitness(proliferationrate)ofindividuals.Increasedproliferationwithincreasedpopulationsize impliescooperativeinteractions.Acontrastingprincipleinecosystemsispopulation?carryingcapacity?which describesadecreaseingrowthrateswithincreasingpopulationsize,duetocompetitionforlimitedresources. Whiletheconceptofcarryingcapacityhasbeenstudiedintumors(whichmaybecomelimitedinnutrientsor oxygen),theAlleeeffecthasbeenalmostentirelyoverlooked.Alleeeffectsaresignificantinsmallpopulations andthusmaybecriticaltounderstandingtheearlieststepsintumoriniation.Toinvestigatethefundamental contributionoftheAlleeeffectontumorecosystemsrequiresthenovelexperimentaldesignsandintegrationof quantitativeexperimentalmeasurementswithmathematicalmodeling.Theoverallgoalofthisprojectisto dissectthecontributionofpopulationsizeandcell-cellcommunicationinafewselected,well-suitedtumorcell linesthroughquantitativesingle-cellresolution,real-timemonitoringofcellpopulations.Mathematicalmodels ofgrowthkineticswillshowthattheAlleeeffectandcell-cellcommunicationhasconsequencesonasingle cancercell?sdecisiontoinitiateagrowingtumorortostaydormant.Thesecommunicationnetworkswillbe furthermappedbyidentificationofspecificparacrinefactorsandreceptors.Disruptionofthecommunication networkthatestablishesaproliferativetumorwillbeperformedbytargetingspecificcellsubpopulation interactions.Perturbationswillincludedepletionofspecificcellsubtypes,manipulationofoverallparacrine signaling,andblockingofspecificligand-receptorcombinationsoninteractingspecies.Thesestrategiesmay benoveltoolstotriggertumorcellpopulationcollapse.Population-leveleffectsinanascenttumorpopulation havenotbeenquantitativelyexploredandmayexplainthephenomenonofcriticalthresholdsanddefinea mechanisticroleforintratumorheterogeneity.Thisprojectfocusesonafundamentalgenericprinciplethatis broadlyapplicableinmanycontextsandthuscouldcomplementandenrichthemodelingeffortsofthecancer researchcommunity.

Public Health Relevance

Withaging,individualsaccumulatenumerousmicroscopiclesionsinthebreast,prostate,thyroid andothertissues;?themajorityofthesemicroscopiclesionsdonotprogresstoinvasivetumors. Hereweinvestigatethetransitionattumorinitiationwiththegoalofunderstandinghowto preventearlylesionsfromundergoingproliferativegrowth.Westudytheroleoftumorcell heterogeneityincontrollingthetransitionfromindolentmicrolesionstoinvasivetumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA226258-02
Application #
9644521
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Zahir, Nastaran Z
Project Start
2018-02-07
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

  Institution

Name
University of Texas Austin
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759