Modeling Evolutionary Dynamics of Epigenetic Mutations in Hierarchically Organized Tumors 英文参考文献.docVIP

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Modeling Evolutionary Dynamics of Epigenetic Mutations in Hierarchically Organized Tumors 英文参考文献.doc

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Modeling Evolutionary Dynamics of Epigenetic Mutations in Hierarchically Organized Tumors 英文参考文献

ModelingEvolutionaryDynamicsofEpigenetic MutationsinHierarchicallyOrganizedTumors AndreaSottoriva1*,LouisVermeulen2*,SimonTavare′1 1Computational Biology Group, University of Cambridge, CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom, 2Laboratory for ExperimentalOncologyandRadiobiology(LEXOR),CenterforExperimentalMolecularMedicine(CEMM),AcademicalMedicalCenter(AMC),Amsterdam,TheNetherlands Abstract Thecancerstemcell(CSC)conceptisahighlydebatedtopicincancerresearch.Whileexperimentalevidenceinfavorofthe cancerstemcelltheoryisapparentlyabundant,theresultsareoftencriticizedasbeingdifficulttointerpret.Animportant reasonforthisisthatmostexperimentaldatathatsupportthismodelrelyontransplantationstudies.Inthisstudyweusea novelcellularPottsmodeltoelucidatethedynamicsofestablishedmalignanciesthataredrivenbyasmallsubsetofCSCs. OurresultsdemonstratethatepigeneticmutationsthatoccurduringmitosisdisplayhighlyaltereddynamicsinCSC-driven malignanciescomparedtoaclassical,non-hierarchicalmodelofgrowth.Inparticular,theheterogeneityobservedinCSC- driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation) sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionaryfeaturesthatcanbeconsideredbeneficialduringtumorprogression.Besidesanincreasedheterogeneitythey alsoexhibitpropertiesthatallowtheescapeofclonesfromlocalfitnesspeaks.Thisleadstomoreaggressivephenotypesin thelongrunandmakestheneoplasmmoreadaptabletostringentselectiveforcessuchascancertreatment.Indeedwhen therapyisappliedtheclonelandscapeoftheregrowntumorismoreaggressivewithrespecttotheprimarytumor,whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamentalpropertiesof(non-)hierarchica