2016
A generic, cost-effective, and scalable cell lineage analysis platform
Biezuner T, Spiro A, Raz O, Amir S, Milo L, Adar R, Chapal-Ilani N, Berman V, Fried Y, Ainbinder E, Cohen G, Barr H, Halaban R, Shapiro E. A generic, cost-effective, and scalable cell lineage analysis platform. Genome Research 2016, 26: 1588-1599. PMID: 27558250, PMCID: PMC5088600, DOI: 10.1101/gr.202903.115.Peer-Reviewed Original ResearchMeSH KeywordsAlgorithmsCell Line, TumorCell LineageCells, CulturedHumansMaleMicrofluidicsMiddle AgedSequence Analysis, DNASingle-Cell AnalysisConceptsLineage analysisSingle cell lineage analysisSingle-cell sequencing dataSingle-cell genomicsCurrent sequencing-based methodsIndividual cellsCell lineage analysisSingle-cell sequencingSequencing-based methodsLineage treesSequencing dataLineage relationsCellsTreesGenomicsAnalysis platformInput cellsSequencingBulk analysisVivoDiscoveryLandscapeAMPK promotes tolerance to Ras pathway inhibition by activating autophagy
Sanduja S, Feng Y, Mathis RA, Sokol ES, Reinhardt F, Halaban R, Gupta PB. AMPK promotes tolerance to Ras pathway inhibition by activating autophagy. Oncogene 2016, 35: 5295-5303. PMID: 27041569, PMCID: PMC6086350, DOI: 10.1038/onc.2016.70.Peer-Reviewed Original ResearchConceptsCellular energy sensor AMPEnergy sensor AMPPathway inhibitorTargeted inhibitorsRas-Raf pathwayDrug-tolerant cellsPathway inhibitionOncogenic RasProtein kinaseRaf signalingRas pathway inhibitionReduced growthAMPKAutophagyPathway mutationsCancer cellsResistant cellsKey mechanismPathwayInhibitorsCellsToleranceKinaseSignalingInhibition
2015
Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation
Kim H, Frederick DT, Levesque MP, Cooper ZA, Feng Y, Krepler C, Brill L, Samuels Y, Hayward NK, Perlina A, Piris A, Zhang T, Halaban R, Herlyn MM, Brown KM, Wargo JA, Dummer R, Flaherty KT, Ronai Z. Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation. Cell Reports 2015, 11: 1458-1473. PMID: 26027934, PMCID: PMC4681438, DOI: 10.1016/j.celrep.2015.04.049.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorChromatography, LiquidDown-RegulationDrug Resistance, NeoplasmEnzyme InhibitorsFemaleHeterograftsHumansImmunoblottingImmunohistochemistryImmunoprecipitationJanus Kinase 1Mass SpectrometryMelanomaMiceMice, NudeProto-Oncogene Proteins B-rafRNA, Small InterferingTransfectionUbiquitin-Protein LigasesConceptsBRAF inhibitorsRTK expressionReceptor tyrosine kinasesRemarkable clinical responsesBRAFi-resistant melanomasInhibition of JAK1BRAFi-resistant tumorsClinical responseCombination therapyMost tumorsBRAF mutationsTumor specimensVivo xenograftsBRAFi resistanceMelanoma cellsElevated expressionMelanomaEGFRAdaptive resistanceTumorsRNF125MITF expressionTyrosine kinaseJAK1DownregulationPLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis
Jilaveanu LB, Parisi F, Barr ML, Zito CR, Cruz-Munoz W, Kerbel RS, Rimm DL, Bosenberg MW, Halaban R, Kluger Y, Kluger HM. PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis. Clinical Cancer Research 2015, 21: 2138-2147. PMID: 25316811, PMCID: PMC4397107, DOI: 10.1158/1078-0432.ccr-14-0861.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBrain NeoplasmsCell Line, TumorFemaleFluorescent Antibody TechniqueGene Expression ProfilingHumansImage Processing, Computer-AssistedIntracellular Signaling Peptides and ProteinsMaleMelanomaMiddle AgedNeoplasm InvasivenessTissue Array AnalysisTranscriptomeYoung AdultConceptsCell line modelsBlood-brain barrierBrain metastasesGene expression profilesGene expression profilingExpression profilingExpression profilesPLEKHA5Brain metastasis-free survivalA375P cellsQuantitative immunofluorescenceEarly brain metastasisMelanoma brain metastasesMetastasis-free survivalProfile of patientsPotential mediatorsProtein levelsMetastatic melanoma casesEarly developmentMelanoma cellsKnockdownDecrease proliferationBBB transmigrationExtracerebral sitesMetastatic sitesPDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets
Scortegagna M, Lau E, Zhang T, Feng Y, Sereduk C, Yin H, De SK, Meeth K, Platt JT, Langdon CG, Halaban R, Pellecchia M, Davies MA, Brown K, Stern DF, Bosenberg M, Ronai ZA. PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets. Cancer Research 2015, 75: 1399-1412. PMID: 25712345, PMCID: PMC4383687, DOI: 10.1158/0008-5472.can-14-2785.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzoatesBridged Bicyclo Compounds, HeterocyclicCell Line, TumorDrug Screening Assays, AntitumorG1 Phase Cell Cycle CheckpointsHumansImmediate-Early ProteinsIndazolesLymphatic MetastasisMelanomaMice, KnockoutMolecular Targeted TherapyProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene Proteins B-rafPyrimidinesPyruvate Dehydrogenase Acetyl-Transferring KinaseSkinSkin NeoplasmsConceptsPDK1 inhibitionAGC kinase familySynthetic lethal screenCell cycle arrestPhase cell cycle arrestPigmentation genesPDK1 activityG1 phase cell cycle arrestSuppress melanoma growthKinase familyTherapeutic targetMelanoma growthPDK1PTEN genotypePI3KMelanoma developmentPotential therapeutic targetK inhibitionPharmacologic inhibitionDevelopment of melanomaPan-PI3K inhibitionBRAF-mutant melanomaSGK3GenesMelanoma cells
2014
Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors
Choi J, Landrette SF, Wang T, Evans P, Bacchiocchi A, Bjornson R, Cheng E, Stiegler AL, Gathiaka S, Acevedo O, Boggon TJ, Krauthammer M, Halaban R, Xu T. Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors. Pigment Cell & Melanoma Research 2014, 27: 253-262. PMID: 24283590, PMCID: PMC4065135, DOI: 10.1111/pcmr.12197.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceCell Line, TumorCell ProliferationDNA Transposable ElementsDrug Resistance, NeoplasmHumansIndolesMAP Kinase Signaling SystemMelanomaModels, MolecularMolecular Sequence DataMutagenesis, InsertionalMutant ProteinsMutationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSulfonamidesVemurafenibConceptsBRAF mutationsNovel BRAF mutationBRAF inhibitorsNext-generation BRAF inhibitorsPLX4032-resistant melanoma cellsMelanoma cellsMelanoma patient survivalHuman prostate cancerBRAF mutant cellsWhole-exome sequencingMelanoma patientsPatient survivalClinical trialsProstate cancerRAF inhibitorsOncogenic mutationsNew screening approachRelevant aberrationsInhibitorsCellsMutationsScreening approachNovel RAF inhibitorsPatientsPLX8394
2012
Integrated analysis of tumor samples sheds light on tumor heterogeneity.
Parisi F, Micsinai M, Strino F, Ariyan S, Narayan D, Bacchiocchi A, Cheng E, Xu F, Li P, Kluger H, Halaban R, Kluger Y. Integrated analysis of tumor samples sheds light on tumor heterogeneity. The Yale Journal Of Biology And Medicine 2012, 85: 347-61. PMID: 23012583, PMCID: PMC3447199.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorChromosome MappingChromosomes, HumanDNA Copy Number VariationsEvolution, MolecularGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, NeoplasmHumansIntercellular Signaling Peptides and ProteinsKaryotypingMelanomaMutationOligonucleotide Array Sequence AnalysisPolymorphism, Single NucleotideProto-Oncogene Proteins B-rafConceptsHigh-throughput profilingGene expression levelsExpression levelsDifferent gene expression levelsGene expression profilingCopy number analysisExpression profilingSNP arrayPathway analysisCopy number statusWnt pathwayTumor samplesNumber alteration profilesTumor heterogeneityTumor evolutionCopy number alteration profilesGenomic aberrationsIntegrated analysisCell linesTumor subclonesNumber analysisNumber statusProfilingDriver mutationsRecurrent associationPreexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors
Shi H, Moriceau G, Kong X, Koya RC, Nazarian R, Pupo GM, Bacchiocchi A, Dahlman KB, Chmielowski B, Sosman JA, Halaban R, Kefford RF, Long GV, Ribas A, Lo RS. Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors. Cancer Discovery 2012, 2: 414-424. PMID: 22588879, PMCID: PMC3594852, DOI: 10.1158/2159-8290.cd-12-0022.Peer-Reviewed Original ResearchConceptsBRAF inhibitorsActivating mutationsObjective tumor responseMEK1/2 inhibitorMEK1 mutationsP-ERK1/2 levelsBRAF-mutant melanomaMelanoma cell linesAdvanced melanomaAntitumor responseExon 3 mutationsTumor responseDisease progressionMelanomaBRAFi resistanceDrug sensitivitySignificant alterationsPatientsCell linesInhibitorsBaselineMutationsExon 3Widespread use
2011
Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma
Tworkoski K, Singhal G, Szpakowski S, Zito CI, Bacchiocchi A, Muthusamy V, Bosenberg M, Krauthammer M, Halaban R, Stern DF. Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma. Molecular Cancer Research 2011, 9: 801-812. PMID: 21521745, PMCID: PMC3117976, DOI: 10.1158/1541-7786.mcr-10-0512.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisCell Line, TumorCell MovementCell ProliferationErbB ReceptorsGene Expression Regulation, NeoplasticGene Knockdown TechniquesHEK293 CellsHumansInfant, NewbornMelanocytesMelanomaPhosphoproteinsPhosphorylationProteomicsReceptor Protein-Tyrosine KinasesReceptor, IGF Type 2RNA, Small InterferingSignal TransductionSkin NeoplasmsSTAT3 Transcription FactorConceptsTherapeutic targetReceptor tyrosine kinasesMelanoma cellsPotential therapeutic targetIdentifies potential therapeutic targetsActive receptor tyrosine kinasesTyrosine kinaseMelanoma cell migrationReceptor expressionBreast cancerAxl knockdownAutocrine circuitTherapeutic interventionsCancer subtypesReceptor tyrosine kinase activationTyrosine kinase activationNovel targetActivated receptorsAxlRNA knockdownMelanomaCell migrationHER3KnockdownIGF1RDetecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies
Parisi F, Ariyan S, Narayan D, Bacchiocchi A, Hoyt K, Cheng E, Xu F, Li P, Halaban R, Kluger Y. Detecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies. BMC Genomics 2011, 12: 230. PMID: 21569352, PMCID: PMC3114747, DOI: 10.1186/1471-2164-12-230.Peer-Reviewed Original ResearchConceptsCopy number statusMelanoma samplesSingle nucleotide polymorphism arrayHigh-throughput technologiesNext-generation sequencing dataHigh-throughput techniquesCopy number profilesHigh-throughput assaysNucleotide polymorphism arrayNumber statusCopy number alterationsTranscriptome sequencingNext-generation sequencingRNA-seqSingle exonSNP arraySequencing dataMelanoma cell linesNumerous aberrationsPolymorphism arrayNovel aberrationsNumber alterationsSubclonal heterogeneitySitu hybridizationAllelic imbalance
2010
Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma
Rubinstein JC, Tran N, Ma S, Halaban R, Krauthammer M. Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma. BMC Medical Genomics 2010, 3: 4. PMID: 20144234, PMCID: PMC2843643, DOI: 10.1186/1755-8794-3-4.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntimetabolites, AntineoplasticAzacitidineCell Line, TumorCpG IslandsDecitabineDNA MethylationDNA Modification MethylasesEnzyme InhibitorsEpigenesis, GeneticFemaleGene Expression ProfilingGenome, HumanHumansMaleMelanomaMiddle AgedPromoter Regions, GeneticTumor Suppressor ProteinsUp-RegulationConceptsHigh CpG contentCpG contentGenome-wide gene expression dataMethylation levelsPromoter CpG contentUp-regulates gene expressionGenome-wide methylationGenome-wide dataLow CpG contentMelanoma cell strainsGene expression dataTumor suppressor geneCytosine analog 5Lower methylation levelsTranscriptional silencingMethylated promotersHigher methylation levelsBisulfite sequencingDNA methylationCpG methylationDNA methyltransferaseGenomic hypomethylationPromoter characteristicsSpecific genesGene expression
2009
Integrative Analysis of Epigenetic Modulation in Melanoma Cell Response to Decitabine: Clinical Implications
Halaban R, Krauthammer M, Pelizzola M, Cheng E, Kovacs D, Sznol M, Ariyan S, Narayan D, Bacchiocchi A, Molinaro A, Kluger Y, Deng M, Tran N, Zhang W, Picardo M, Enghild JJ. Integrative Analysis of Epigenetic Modulation in Melanoma Cell Response to Decitabine: Clinical Implications. PLOS ONE 2009, 4: e4563. PMID: 19234609, PMCID: PMC2642998, DOI: 10.1371/journal.pone.0004563.Peer-Reviewed Original ResearchConceptsDNA damage responseMelanoma cell responseDamage responseGene expressionIntegrative analysisDifferential gene expressionMelanoma cell strainsGene expression profilesDNA promoter methylationP53-independent mannerHistone modificationsImproved combination therapiesEpigenetic modifiersTGFbeta pathwayBioinformatics analysisProtein stabilityEpigenetic modulationResistant melanoma cellsExpression profilesGrowth arrestPromoter methylationCancer cellsCell strainsProteasome inhibitorsPTEN mutations
2004
Novel tyramide‐based tyrosinase assay for the detection of melanoma cells in cytological preparations
Angeletti C, Khomitch V, Halaban R, Rimm DL. Novel tyramide‐based tyrosinase assay for the detection of melanoma cells in cytological preparations. Diagnostic Cytopathology 2004, 31: 33-37. PMID: 15236262, DOI: 10.1002/dc.20051.Peer-Reviewed Original Research