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