Featured Publications
Strand-resolved mutagenicity of DNA damage and repair
Anderson C, Talmane L, Luft J, Connelly J, Nicholson M, Verburg J, Pich O, Campbell S, Giaisi M, Wei P, Sundaram V, Connor F, Ginno P, Sasaki T, Gilbert D, López-Bigas N, Semple C, Odom D, Aitken S, Taylor M. Strand-resolved mutagenicity of DNA damage and repair. Nature 2024, 630: 744-751. PMID: 38867042, PMCID: PMC11186772, DOI: 10.1038/s41586-024-07490-1.Peer-Reviewed Original ResearchConceptsDNA damageDNA damage-induced mutationsSingle-base resolutionCancer genome evolutionDamage-induced mutationsRepair of DNA damageNucleotide excision repairGenome evolutionMultiple distinct mutationsDNA accessibilityGenomic conditionsReplicative strandProcess genomesDNA base damageTranslesion polymerasesExcision repairDNAMutation patternsMutationsBase damageRepair efficiencyStrandsAlkyl adductsReplicationIdentity fidelityDNA lesion bypass and the stochastic dynamics of transcription-coupled repair
Nicholson M, Anderson C, Odom D, Aitken S, Taylor M. DNA lesion bypass and the stochastic dynamics of transcription-coupled repair. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2403871121. PMID: 38717857, PMCID: PMC11098089, DOI: 10.1073/pnas.2403871121.Peer-Reviewed Original ResearchConceptsTranscription-coupled repairRNA polymerase IIDistribution of mutationsStalling of RNA polymerase IITranscription-coupled repair (TCRDNA damageGene expressionBarriers to gene expressionSites of DNA damageGenome-wide distributionBarrier to transcriptionDamaged DNA strandMammalian model systemsDNA lesion bypassGene bodiesPolymerase IIRNA polymeraseGenetic integrityGene productsDNA base damageLesion bypassAlkylation damageDNA strandsBypass lesionsMutationsSingle-mitosis dissection of acute and chronic DNA mutagenesis and repair
Ginno P, Borgers H, Ernst C, Schneider A, Behm M, Aitken S, Taylor M, Odom D. Single-mitosis dissection of acute and chronic DNA mutagenesis and repair. Nature Genetics 2024, 56: 913-924. PMID: 38627597, PMCID: PMC11096113, DOI: 10.1038/s41588-024-01712-y.Peer-Reviewed Original ResearchConceptsMutational processesUV damageGenome evolutionGenome-wideTranscribed regionsGenome replicationCancer genomesUV mutationCC dinucleotidesDNA mutagenesisSister cellsDriving evolutionGenomeMutagenesisPunctuated burstsSingle cellsRounds of genome replicationMutationsStrandsCellsMitosisDinucleotideSisterROSReplicationTitration of RAS alters senescent state and influences tumour initiation
Chan A, Zhu H, Narita M, Cassidy L, Young A, Bermejo-Rodriguez C, Janowska A, Chen H, Gough S, Oshimori N, Zender L, Aitken S, Hoare M, Narita M. Titration of RAS alters senescent state and influences tumour initiation. Nature 2024, 633: 678-685. PMID: 39112713, PMCID: PMC11410659, DOI: 10.1038/s41586-024-07797-z.Peer-Reviewed Original ResearchConceptsTumor typesOncogenic RAS-induced senescenceInfluence tumor initiationProgenitor-like featuresTumor-initiating phenotypeSingle-cell RNA sequencing analysisModel in vivoHCC subclassesModel in vitroHepatocellular carcinomaTumor suppressor mechanismEarly tumorigenesisTumor initiationEarly-onsetProgenitor featuresInduce tumorsSuppressor mechanismTumorLate-onsetRNA sequencing analysisOncogenic stressRas-induced senescenceIn vivoMolecular signaturesOncogene dosagePervasive lesion segregation shapes cancer genome evolution
Aitken S, Anderson C, Connor F, Pich O, Sundaram V, Feig C, Rayner T, Lukk M, Aitken S, Luft J, Kentepozidou E, Arnedo-Pac C, Beentjes S, Davies S, Drews R, Ewing A, Kaiser V, Khamseh A, López-Arribillaga E, Redmond A, Santoyo-Lopez J, Sentís I, Talmane L, Yates A, Semple C, López-Bigas N, Flicek P, Odom D, Taylor M. Pervasive lesion segregation shapes cancer genome evolution. Nature 2020, 583: 265-270. PMID: 32581361, PMCID: PMC7116693, DOI: 10.1038/s41586-020-2435-1.Peer-Reviewed Original ResearchConceptsChromosome-scale phasingDNA lesionsAcquisition of oncogenic mutationsAlternative allelesGenetic diversityMultiple cell generationsCancer genomesLesion segregationDNA replicationMutagenic DNA lesionsDaughter cellsBase pairsCell divisionCell cycleExogenous mutagensHuman cellsOncogenic selectionOncogenic mutationsMouse liver tumorsDNACell generationDNA base pairsMutationsCellsGenomeMutational landscape of a chemically-induced mouse model of liver cancer
Connor F, Rayner T, Aitken S, Feig C, Lukk M, Santoyo-Lopez J, Odom D. Mutational landscape of a chemically-induced mouse model of liver cancer. Journal Of Hepatology 2018, 69: 840-850. PMID: 29958939, PMCID: PMC6142872, DOI: 10.1016/j.jhep.2018.06.009.Peer-Reviewed Original ResearchConceptsSomatic single nucleotide variantsCarcinogen-induced mouse modelsModel of hepatocellular carcinomaMouse model of liver cancerMutational landscape of tumorsModel of liver cancerLandscape of tumorsHepatocellular carcinomaMouse modelMutational landscapeLiver cancerOncogenic drivers of HCCLiver tumorsNon-synonymous point mutationsGenomic alterationsHuman diseasesTruncating mutations of APCMutational signaturesMouse model of hepatocellular carcinomaSingle nucleotide variantsDrivers of hepatocellular carcinomaChemically-induced mouse modelCopy number alterationsCOSMIC mutational signaturesActivating hotspot mutationsCTCF maintains regulatory homeostasis of cancer pathways
Aitken S, Ibarra-Soria X, Kentepozidou E, Flicek P, Feig C, Marioni J, Odom D. CTCF maintains regulatory homeostasis of cancer pathways. Genome Biology 2018, 19: 106. PMID: 30086769, PMCID: PMC6081938, DOI: 10.1186/s13059-018-1484-3.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCCCTC-Binding FactorCell LineChromatinDNA, NeoplasmEnhancer Elements, GeneticFemaleFibroblastsGene Expression Regulation, NeoplasticGenomeHemizygoteHomeostasisHumansLiver Neoplasms, ExperimentalMiceMice, Inbred C57BLMice, TransgenicProtein BindingSignal TransductionUterine NeoplasmsConceptsTranscriptional regulationIntra-TAD interactionsSteady-state gene expressionCancer-related pathwaysMammalian genomesCTCF occupancyGenome functionChromatin loopsEvolutionary conservationChromatin structureGenomic dysregulationRegulatory domainHemizygous cellsEpigenomic profilingCTCFCTCF expressionMammalian cellsExpressed genesAffinity binding eventsTranscriptional alterationsGene expressionMouse lineagesCancer pathwaysMouse model systemHuman cancers
2024
Novel immunotherapeutics against LGR5 to target multiple cancer types
Chen H, Mueller N, Stott K, Kapeni C, Rivers E, Sauer C, Beke F, Walsh S, Ashman N, O’Brien L, Rafati Fard A, Ghodsinia A, Li C, Joud F, Giger O, Zlobec I, Olan I, Aitken S, Hoare M, Mair R, Serrao E, Brenton J, Garcia-Gimenez A, Richardson S, Huntly B, Spring D, Skjoedt M, Skjødt K, de la Roche M, de la Roche M. Novel immunotherapeutics against LGR5 to target multiple cancer types. EMBO Molecular Medicine 2024, 16: 2233-2261. PMID: 39169164, PMCID: PMC11393416, DOI: 10.1038/s44321-024-00121-2.Peer-Reviewed Original ResearchConceptsHepatocellular carcinomaColorectal cancerTarget multiple cancer typesBispecific T-cell engagerCell killing in vitroChimeric antigen receptorT-cell engagersCancer cells in vitroPre-B-ALLAnti-tumor efficacyCancer cell killing in vitroKilling in vitroCells in vitroAntibody-drug conjugatesMultiple cancer typesLgr5 overexpressionTumor burdenAntigen receptorMurine modelNovel immunotherapeuticsCancer modelsTumor cellsEffective modalityEffective tumorLgr5
2020
IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis
Siersbæk R, Scabia V, Nagarajan S, Chernukhin I, Papachristou E, Broome R, Johnston S, Joosten S, Green A, Kumar S, Jones J, Omarjee S, Alvarez-Fernandez R, Glont S, Aitken S, Kishore K, Cheeseman D, Rakha E, D'Santos C, Zwart W, Russell A, Brisken C, Carroll J. IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis. Cancer Cell 2020, 38: 412-423.e9. PMID: 32679107, PMCID: PMC7116707, DOI: 10.1016/j.ccell.2020.06.007.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, HormonalBreast NeoplasmsEnhancer Elements, GeneticEstrogen Receptor alphaFemaleFulvestrantGene Expression ProfilingGene Expression Regulation, NeoplasticHumansInterleukin-6Kaplan-Meier EstimateMCF-7 CellsMice, Inbred NODMice, KnockoutMice, SCIDNeoplasm MetastasisSignal TransductionSTAT3 Transcription FactorXenograft Model Antitumor AssaysConceptsEstrogen receptor aInhibition of STAT3 activationOncogenic pathwaysBreast cancer invasionSTAT3 activationTranscriptional programsDownstream effector STAT3STAT3IL6/STAT3 signalingIndependent of ERCancer invasionER enhancementER-targeted therapiesBreast cancerCytokine interleukin-6Interleukin-6PathwayIL6/STAT3Receptor AClustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains
Kentepozidou E, Aitken S, Feig C, Stefflova K, Ibarra-Soria X, Odom D, Roller M, Flicek P. Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains. Genome Biology 2020, 21: 5. PMID: 31910870, PMCID: PMC6945661, DOI: 10.1186/s13059-019-1894-x.Peer-Reviewed Original ResearchConceptsTopologically associating domains boundariesTopologically associating domainsCTCF sitesCTCF bindingConservation of topologically associating domainsGenome-wide binding profilesHigher-order chromatin structureCTCF binding patternsCTCF ChIP-seqGene transcription start siteHigher-order genome structureCTCF binding sitesNatural genetic variationTranscription start siteSpecies-specific sitesCohesin stabilizationTAD boundariesChIP-seqGenomic structureStart siteChromatin structureTranscriptional regulationCTCFAssociation domainGenetic variation
2018
Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry
Quiros-Gonzalez I, Tomaszewski M, Aitken S, Ansel-Bollepalli L, McDuffus L, Gill M, Hacker L, Brunker J, Bohndiek S. Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry. British Journal Of Cancer 2018, 118: 1098-1106. PMID: 29576623, PMCID: PMC5931091, DOI: 10.1038/s41416-018-0033-x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiological MimicryBreast NeoplasmsCell Line, TumorDrug MonitoringFemaleHumansMammary Neoplasms, ExperimentalMCF-7 CellsMiceMice, Inbred BALB CMice, NudeNeoplasm StagingNeovascularization, PathologicOxygen ConsumptionPhotoacoustic TechniquesSensitivity and SpecificityTomographyTumor HypoxiaXenograft Model Antitumor AssaysConceptsMDA-MB-231Breast cancer modelCancer modelsVascular mimicryOrthotopic breast cancer xenograftsVascular phenotypeMurine breast cancer modelMDA-MB-231 tumorsMCF-7Consistent with angiogenesisMCF-7 tumorsTotal hemoglobinBreast cancer xenograftsBreast tumor modelEx vivo analysisNO serum levelsTumor oxygenationEstrogen-independentCancer xenograftsSerum levelsEstrogen-dependentTherapeutic responseBreast tumorsTumor modelClinical trials
2016
Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis
Ernst C, Pike J, Aitken S, Long H, Eling N, Stojic L, Ward M, Connor F, Rayner T, Lukk M, Klose R, Kutter C, Odom D. Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis. ELife 2016, 5: e20235. PMID: 27855777, PMCID: PMC5161449, DOI: 10.7554/elife.20235.Peer-Reviewed Original ResearchConceptsHuman chromosomeMale meiosisTranscription factor bindingGermline transmissionNon-methylated DNATolerance of aneuploidyStudy chromosomal abnormalitiesMammalian spermatogenesisMapped transcriptsTranscription initiationFactor bindingDevelopmental machineryChromatin condensationTestis architectureAneuploid miceExogenous DNAAneuploid offspringMale sterilityChromosomeAdult tissuesSpermatogenesisMeiosisChromosomal abnormalitiesEnhanced activityTranscription
2008
β2-Adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms
Aitken S, Landao-Bassonga E, Ralston S, Idris A. β2-Adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms. Archives Of Biochemistry And Biophysics 2008, 482: 96-103. PMID: 19059194, DOI: 10.1016/j.abb.2008.11.012.Peer-Reviewed Original ResearchConceptsExpression of RANK-LBeta2-adrenoceptorOsteoclast formationBeta-adrenoceptorIncreased expression of RANK-LBone resorptionInfluence bone mineral densityOsteoclast differentiation in vitroRegulation of bone massBone mineral densityEffect of noradrenalineRANK-LSympathetic nervous systemInduce osteoclast formationOsteoblasts co-culturedDifferentiation in vitroAgonist isoprenalineMineral densityBeta3-adrenoceptorFracture riskLevels of beta1Beta-adrenoreceptorsBone massPharmacological agonistsOsteoblast growth