Featured Publications
Oncogene-like addiction to aneuploidy in human cancers
Girish V, Lakhani A, Thompson S, Scaduto C, Brown L, Hagenson R, Sausville E, Mendelson B, Kandikuppa P, Lukow D, Yuan M, Stevens E, Lee S, Schukken K, Akalu S, Vasudevan A, Zou C, Salovska B, Li W, Smith J, Taylor A, Martienssen R, Liu Y, Sun R, Sheltzer J. Oncogene-like addiction to aneuploidy in human cancers. Science 2023, 381: eadg4521. PMID: 37410869, PMCID: PMC10753973, DOI: 10.1126/science.adg4521.Peer-Reviewed Original Research
2024
An elevated rate of whole-genome duplications in cancers from Black patients
Brown L, Hagenson R, Koklič T, Urbančič I, Qiao L, Strancar J, Sheltzer J. An elevated rate of whole-genome duplications in cancers from Black patients. Nature Communications 2024, 15: 8218. PMID: 39300140, PMCID: PMC11413164, DOI: 10.1038/s41467-024-52554-5.Peer-Reviewed Original ResearchConceptsWhole-genome duplicationRate of whole-genome duplicationsBlack patientsSelf-reported Black patientsChromosomal copy number changesRates of cancer mortalityCopy number changesInfluence racial disparitiesAssociated with environmental exposuresCancer mortalityGenomic eventsAssociated with shorter patient survivalCancer outcomesRacial disparitiesGenomic alterationsShorter patient survivalBlack individualsWhite patientsEnvironmental exposuresRacial groupsCell culturesAggressive diseasePatient survivalLung cancerEnhanced metastasisThe next Nobel Prize in chemistry or in physiology or medicine
Kadoch C, Sheltzer J, Yin H. The next Nobel Prize in chemistry or in physiology or medicine. Cell Chemical Biology 2024, 31: 1566-1567. PMID: 39303696, DOI: 10.1016/j.chembiol.2024.08.013.Peer-Reviewed Original ResearchEvolving copy number gains promote tumor expansion and bolster mutational diversification
Wang Z, Xia Y, Mills L, Nikolakopoulos A, Maeser N, Dehm S, Sheltzer J, Sun R. Evolving copy number gains promote tumor expansion and bolster mutational diversification. Nature Communications 2024, 15: 2025. PMID: 38448455, PMCID: PMC10918155, DOI: 10.1038/s41467-024-46414-5.Peer-Reviewed Original ResearchConceptsSomatic copy number alterationsMutational diversificationCopy numberGenome sequenced samplesCopy number alterationsCopy number gainGenome segmentsPromote tumor expansionGenome doublingPopulation expansionSequenced samplesFitness effectsTumor typesCancer evolutionTumor expansionClonal expansionGenomeDiversification
2023
Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor
Bhattacharjee D, Bakar J, Chitnis S, Sausville E, Ashtekar K, Mendelson B, Long K, Smith J, Heppner D, Sheltzer J. Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor. Cell Chemical Biology 2023, 30: 1211-1222.e5. PMID: 37827156, PMCID: PMC10715717, DOI: 10.1016/j.chembiol.2023.09.013.Peer-Reviewed Original ResearchAneuploidy in human cancer: new tools and perspectives
Lakhani A, Thompson S, Sheltzer J. Aneuploidy in human cancer: new tools and perspectives. Trends In Genetics 2023, 39: 968-980. PMID: 37778926, PMCID: PMC10715718, DOI: 10.1016/j.tig.2023.09.002.Peer-Reviewed Original ResearchConceptsSpecific chromosomal changesClinical prognosisConsequences of aneuploidyTreatment strategiesFeature of cancerIsogenic cell linesDosage-sensitive genesShort palindromic repeatsCancer developmentCopy number imbalancesMalignant growthHuman cancersAneuploid chromosomesCell linesPalindromic repeatsCancerChromosomal changesAneuploidyNumber imbalancesPrognosis
2022
Extensive protein dosage compensation in aneuploid human cancers
Schukken KM, Sheltzer J. Extensive protein dosage compensation in aneuploid human cancers. Genome Research 2022, 32: 1254-1270. PMID: 35701073, PMCID: PMC9341510, DOI: 10.1101/gr.276378.121.Peer-Reviewed Original ResearchConceptsDosage compensationPost-translational regulatory mechanismsProtein complex subunitsCopy numberHuman cancersCell cycle genesEffects of aneuploidyMajority of proteinsChromosome copy numberProtein expression dataKey driver genesChromosome copy number changesExpression of oncogenesCopy number changesKey cancer driversComplex subunitsCycle genesGene groupsCancer driversCancer proteomeRegulatory mechanismsTumor suppressorExpression dataDriver genesChromosome gainsGenome-wide identification and analysis of prognostic features in human cancers
Smith JC, Sheltzer JM. Genome-wide identification and analysis of prognostic features in human cancers. Cell Reports 2022, 38: 110569. PMID: 35354049, PMCID: PMC9042322, DOI: 10.1016/j.celrep.2022.110569.Peer-Reviewed Original ResearchConceptsAdverse biomarkersSignificant prognostic biomarkerShorter survival timePromising therapeutic targetPatient survival dataPreclinical cancer researchPrognostic featuresAggressive malignancyClinical trialsPatient outcomesPatient riskPrognostic biomarkerSurvival timeTherapeutic targetSuccessful drug targetsClinical decisionCancerSurvival dataTherapeutic developmentHuman cancersBiomarkersBiomarker analysisDriver genesCancer researchCancer driver genes
2021
Chromosomal instability and aneuploidy as causes of cancer drug resistance
Lukow DA, Sheltzer JM. Chromosomal instability and aneuploidy as causes of cancer drug resistance. Trends In Cancer 2021, 8: 43-53. PMID: 34593353, DOI: 10.1016/j.trecan.2021.09.002.Peer-Reviewed Original ResearchConceptsChromosomal instabilityGene dosage alterationsChromosome copy number changesCopy number changesCell fitnessCancer drug resistanceCellular adaptabilitySelective pressureDrug resistanceTumor evolutionNumber changesDosage alterationsRecent evidenceAneuploidyIntratumoral heterogeneityPoor patient outcomesFitnessHigh levelsUnique vulnerabilitiesResistanceChromosomal instability accelerates the evolution of resistance to anti-cancer therapies
Lukow DA, Sausville EL, Suri P, Chunduri NK, Wieland A, Leu J, Smith JC, Girish V, Kumar AA, Kendall J, Wang Z, Storchova Z, Sheltzer JM. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental Cell 2021, 56: 2427-2439.e4. PMID: 34352222, PMCID: PMC8933054, DOI: 10.1016/j.devcel.2021.07.009.Peer-Reviewed Original ResearchConceptsChromosomal instabilityAnti-cancer therapyCancer cell fitnessAcquisition of aneuploidyChromosome loss eventsSingle-cell sequencingEvolution of resistanceDifferent culture environmentsCellular fitnessPhenotypic plasticityCIN correlatesHuman tumorsCell fitnessHuman cellsStressful environmentsResistant populationsAcquisition of resistanceRecurrent aneuploidyCancer cellsPaclitaxel-resistant cellsCulture environmentAneuploidyPaclitaxel sensitivityFitnessCellsAneuploidy as a promoter and suppressor of malignant growth
Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nature Reviews Cancer 2021, 21: 89-103. PMID: 33432169, DOI: 10.1038/s41568-020-00321-1.Peer-Reviewed Original Research
2020
Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division
Replogle JM, Zhou W, Amaro AE, McFarland JM, Villalobos-Ortiz M, Ryan J, Letai A, Yilmaz O, Sheltzer J, Lippard SJ, Ben-David U, Amon A. Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 30566-30576. PMID: 33203674, PMCID: PMC7720170, DOI: 10.1073/pnas.2009506117.Peer-Reviewed Original ResearchConceptsCell cycle delayG1 cell cycle delayChromosome gainsSingle chromosome gainsCycle delayWhole chromosome gainsCancer Cell Line Encyclopedia (CCLE) datasetsDrug resistanceCell divisionCellular stressEuploid cellsPoor disease outcomeG1 delayPoor patient prognosisS phaseSelective benefitsSlow proliferationChemotherapeutic cisplatinChemotherapeutic resistanceCancer cellsSlowed proliferationChemotherapy treatmentPatient prognosisDisease outcomeAneuploidyDiscovering and validating cancer genetic dependencies: approaches and pitfalls
Lin A, Sheltzer JM. Discovering and validating cancer genetic dependencies: approaches and pitfalls. Nature Reviews Genetics 2020, 21: 671-682. PMID: 32561862, DOI: 10.1038/s41576-020-0247-7.Peer-Reviewed Original ResearchSingle-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer
Vasudevan A, Baruah PS, Smith JC, Wang Z, Sayles NM, Andrews P, Kendall J, Leu J, Chunduri NK, Levy D, Wigler M, Storchová Z, Sheltzer JM. Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer. Developmental Cell 2020, 52: 413-428.e6. PMID: 32097652, PMCID: PMC7354079, DOI: 10.1016/j.devcel.2020.01.034.Peer-Reviewed Original ResearchMeSH KeywordsAneuploidyAnimalsApoptosisCell MovementCell ProliferationChromosomal InstabilityChromosomes, Human, Pair 5Colonic NeoplasmsEpithelial-Mesenchymal TransitionFemaleHumansMaleMembrane ProteinsMiceMice, NudeNeoplasm InvasivenessNucleotidyltransferasesTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsSingle extra chromosomeCell state transitionsCGAS/STING signalingCell linesCopy number dataPartial epithelial-mesenchymal transitionCancer aneuploidyPhenotypic plasticityGenomic plasticitySingle chromosomeEpithelial-mesenchymal transitionMetastasis suppressorChromosomal instabilityExtra chromosomeCertain aneuploidiesDifferent aneuploidiesCancer progressionSpecific aneuploidiesChromosomal gainsChromosomesSTING signalingMetastatic behaviorTumor progressionAneuploidyUniform driver
2019
Micronuclei-based model system reveals functional consequences of chromothripsis in human cells
Kneissig M, Keuper K, de Pagter MS, van Roosmalen MJ, Martin J, Otto H, Passerini V, Sparr A, Renkens I, Kropveld F, Vasudevan A, Sheltzer JM, Kloosterman WP, Storchova Z. Micronuclei-based model system reveals functional consequences of chromothripsis in human cells. ELife 2019, 8: e50292. PMID: 31778112, PMCID: PMC6910827, DOI: 10.7554/elife.50292.Peer-Reviewed Original ResearchConceptsMassive chromosomal rearrangementsChromosomal rearrangementsHuman cellsLamin B1Replication-dependent mechanismModel systemMicronucleus sizeProper assemblyAberrant replicationChromosome shatteringChromosome transferMembrane curvatureNuclear envelopeExtra chromosomeAberrant structuresDNA damageChromosomesGrowth advantageFunctional consequencesCancer cellsAbnormal numberTrisomic cellsCellsChromosomal aberrationsRearrangementOff-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, Sausville EL, Lukow DA, Liu L, Chait AR, Galluzzo ZC, Tucker C, Sheltzer JM. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine 2019, 11 PMID: 31511426, PMCID: PMC7717492, DOI: 10.1126/scitranslmed.aaw8412.Peer-Reviewed Original ResearchConceptsClinical trialsCancer drugsDose-limiting toxicityLack of efficacyDrug Administration approvalNumber of therapiesCancer cell proliferationMultiple cancer typesMechanism of actionClinical benefitAdministration approvalCommon causeTrial failuresSmall molecule inhibitorsClinical testingCDK11 expressionHuman patientsPreclinical settingCancer typesU.S. FoodTarget toxicityNew drugsDrugsCell proliferationDrug-indication pairsGenerating Single Cell–Derived Knockout Clones in Mammalian Cells with CRISPR/Cas9
Giuliano CJ, Lin A, Girish V, Sheltzer JM. Generating Single Cell–Derived Knockout Clones in Mammalian Cells with CRISPR/Cas9. Current Protocols In Molecular Biology 2019, 128: e100. PMID: 31503414, PMCID: PMC6741428, DOI: 10.1002/cpmb.100.Peer-Reviewed Original ResearchConceptsKnockout clonesMammalian cellsCell linesCRISPR/Cas9 technologyGuide RNA designMammalian cell linesGene lossClonal cell linesGene functionProtein functionGene targetingNew cell lineCas9 technologyTargeted geneFunction mutationsInterclonal heterogeneityRNA designSingle cellsSuccessful derivationClonesCRISPRCRISPR deliveryBiological reagentsRapid generationMutations
2018
Systematic identification of mutations and copy number alterations associated with cancer patient prognosis
Smith J, Sheltzer J. Systematic identification of mutations and copy number alterations associated with cancer patient prognosis. ELife 2018, 7: e39217. PMID: 30526857, PMCID: PMC6289580, DOI: 10.7554/elife.39217.Peer-Reviewed Original ResearchConceptsPatient prognosisSuccessful treatment decisionsDriver genesIndependent patient cohortsRobust prognostic biomarkerCancer patient prognosisSignificant prognostic powerSpecific therapeutic vulnerabilitiesSpecific cancer typesPatient cohortWorse outcomesDeadly malignancyPatient riskClinical riskPrognostic biomarkerTreatment decisionsPrognostic powerMolecular alterationsTherapeutic vulnerabilitiesCopy number alterationsCancer typesFocal CNAsTotal aneuploidyGenomic profilesPrognosisMELK expression correlates with tumor mitotic activity but is not required for cancer growth
Giuliano C, Lin A, Smith J, Palladino A, Sheltzer J. MELK expression correlates with tumor mitotic activity but is not required for cancer growth. ELife 2018, 7: e32838. PMID: 29417930, PMCID: PMC5805410, DOI: 10.7554/elife.32838.Peer-Reviewed Original ResearchConceptsMaternal embryonic leucine zipper kinaseTumor mitotic activityCancer typesMitotic activityPoor clinical prognosisBreast cancer cell linesPromising therapeutic targetTriple-negative breast cancer cell linesEmbryonic leucine zipper kinaseMultiple cancer typesLeucine zipper kinaseCancer cell linesCytotoxic chemotherapyAggressive diseaseCancer patientsClinical prognosisMELK expressionTherapeutic targetChemotherapy resistanceCancer growthTumor growthAcute inhibitionMELK inhibitorExpression correlatesCancer-related processes
2017
CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials
Lin A, Giuliano C, Sayles N, Sheltzer J. CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials. ELife 2017, 6: e24179. PMID: 28337968, PMCID: PMC5365317, DOI: 10.7554/elife.24179.Peer-Reviewed Original ResearchConceptsMaternal embryonic leucine zipper kinaseClinical trialsCancer cell linesBasal breast cancer cell linesCancer typesCell linesNovel chemotherapy agentsTriple-negative subtypeCurrent clinical trialsBreast cancer cell linesEmbryonic leucine zipper kinaseLeucine zipper kinaseMELK knockdownBreast cancerChemotherapy agentsPreclinical resultsSmall molecule inhibitorsAnchorage-independent growthMELK inhibitorTarget mechanismsPreclinical target validationTrialsDoubling timeTarget validationInhibitors