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 imbalancesPrognosisRicolinostat is not a highly selective HDAC6 inhibitor
Médard G, Sheltzer J. Ricolinostat is not a highly selective HDAC6 inhibitor. Nature Cancer 2023, 4: 807-808. PMID: 37322365, DOI: 10.1038/s43018-023-00582-3.Peer-Reviewed Original Research
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 gainsSynthesis and Structure–Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold
Li Z, Ishida R, Liu Y, Wang J, Li Y, Gao Y, Jiang J, Che J, Sheltzer JM, Robers MB, Zhang T, Westover KD, Nabet B, Gray NS. Synthesis and Structure–Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold. European Journal Of Medicinal Chemistry 2022, 238: 114433. PMID: 35597007, PMCID: PMC9477540, DOI: 10.1016/j.ejmech.2022.114433.Peer-Reviewed Original ResearchConceptsCyclin-dependent kinasesCell cycle regulationG2/M cell cycle arrestM cell cycle arrestCell cycle arrestCellular functionsCycle regulationCellular assaysCycle arrestTool compoundsNeuronal functionAttractive targetCDK11Drug discoveryMedicinal chemistry modificationsStructure-activity relationshipsSplicingTranscriptionInhibitorsMedicinal chemistry campaignKinaseInhibitionApoptosisMRNARegulationGenome-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 outcomeAneuploidyA CRISPR Competition Assay to Identify Cancer Genetic Dependencies.
Girish V, Sheltzer JM. A CRISPR Competition Assay to Identify Cancer Genetic Dependencies. Bio-protocol 2020, 10: e3682. PMID: 33659353, PMCID: PMC7842800, DOI: 10.21769/bioprotoc.3682.Peer-Reviewed Original ResearchGenetic dependenciesTargeted locusCancer cell fitnessCRISPR/Cas9 systemGene of interestWhole-genome screenAnti-cancer drug developmentCell fitnessNuclease Cas9Mammalian cellsGenome editingGene dependenciesCas9 systemSpecific genesConsequences of lossCompetition assaysCell linesPotential targetGenesLociCancer typesDrug developmentFunction perturbationsCas9CRISPRDiscovering 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 aberrationsRearrangementIncreasing gender diversity in the STEM research workforce
Greider CW, Sheltzer JM, Cantalupo NC, Copeland WB, Dasgupta N, Hopkins N, Jansen JM, Joshua-Tor L, McDowell GS, Metcalf JL, McLaughlin B, Olivarius A, O'Shea EK, Raymond JL, Ruebain D, Steitz JA, Stillman B, Tilghman SM, Valian V, Villa-Komaroff L, Wong JY. Increasing gender diversity in the STEM research workforce. Science 2019, 366: 692-695. PMID: 31699926, DOI: 10.1126/science.aaz0649.Peer-Reviewed Original ResearchGender-based harassmentGender-specific barriersAdvancement of womenDomestic laborPolicy changesWomen's abilitySystemic barriersCultural factorsUnequal distributionU.S. institutionsGender diversityResearch institutionsFunding agenciesProfessional focusHarassmentUnconscious biasesResearch fundingResearch workforceInstitutionsCareerSTEM disciplinesResearch careerScientific careerGovernanceSuccessful strategyOff-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 pairs