Featured Publications
Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake
Haskins JW, Zhang S, Means RE, Kelleher JK, Cline GW, Canfrán-Duque A, Suárez Y, Stern DF. Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. Science Signaling 2015, 8: ra111. PMID: 26535009, PMCID: PMC4666504, DOI: 10.1126/scisignal.aac5124.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorCholesterolFemaleHumansHydroxymethylglutaryl CoA ReductasesLipoproteins, LDLMechanistic Target of Rapamycin Complex 1Multiprotein ComplexesNeuregulin-1Proto-Oncogene Proteins c-aktReceptor, ErbB-4Receptors, LDLSterol Regulatory Element Binding Protein 2TOR Serine-Threonine KinasesConceptsIntracellular domainEGFR family membersLow-density lipoprotein uptakeCholesterol biosynthesisSREBP target genesRapamycin complex 1ErbB4 intracellular domainSite-1 proteaseCholesterol biosynthesis genesSoluble intracellular domainCholesterol biosynthetic pathwayActivation of ErbB4Mammary epithelial cellsInhibition of AktSterol regulatory elementBiosynthesis genesLipoprotein uptakeRegulatory elementsBiosynthetic pathwayTarget genesDevelopmental processesMetabolic remodelingMature formNeuregulin-1Cellular membranesPhosphoproteomic 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 migrationHER3KnockdownIGF1RGenotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening
Held MA, Langdon CG, Platt JT, Graham-Steed T, Liu Z, Chakraborty A, Bacchiocchi A, Koo A, Haskins JW, Bosenberg MW, Stern DF. Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening. Cancer Discovery 2013, 3: 52-67. PMID: 23239741, PMCID: PMC3546137, DOI: 10.1158/2159-8290.cd-12-0408.Peer-Reviewed Original ResearchConceptsMutant BRAF melanomaCyclin-dependent kinase inhibitorBRAF melanomaSmall molecule inhibitorsHigh-throughput drug screeningDrug screeningEGF receptorCombination therapyDrug combinationsMelanoma culturesContext of genotypePairwise combinationsResistance phenotypeCombinatorial drug screeningUnique treatment regimensCombination of statinsVivo xenograftsKinase inhibitorsMutant BRAFMutationsEfficacious drug combinationsPartial responseTreatment regimensRAS mutationsBRAF mutationsMicrocephalin Is a DNA Damage Response Protein Involved in Regulation of CHK1 and BRCA1 * ♦
Xu X, Lee J, Stern DF. Microcephalin Is a DNA Damage Response Protein Involved in Regulation of CHK1 and BRCA1 * ♦. Journal Of Biological Chemistry 2004, 279: 34091-34094. PMID: 15220350, DOI: 10.1074/jbc.c400139200.Peer-Reviewed Original ResearchMeSH KeywordsBlotting, NorthernBlotting, WesternBRCA1 ProteinCell CycleCell Cycle ProteinsCell LineCheckpoint Kinase 1Cytoskeletal ProteinsDNADNA DamageDown-RegulationG2 PhaseGene Expression RegulationGene Expression Regulation, NeoplasticHistonesHumansMicroscopy, FluorescenceMitosisNerve Tissue ProteinsPhosphorylationPlasmidsPrecipitin TestsProtein KinasesProtein Structure, TertiaryRadiation, IonizingRNA, MessengerRNA, Small InterferingConceptsDNA damage-induced cellular responsesDNA damage response proteinsCellular responsesDamage response proteinsNFBD1/MDC1Regulation of BRCA1Regulation of Chk1Radiation-induced fociEndogenous BRCA1BRCT domainFirst geneResponse proteinsTranscript levelsMCPH1Primary microcephalyProteinMicrocephalinChk1Autosomal recessive diseaseBRCA1RegulationRecessive diseaseMDC1PtcbGenesPolo-like Kinase 1 and Chk2 Interact and Co-localize to Centrosomes and the Midbody*
Tsvetkov L, Xu X, Li J, Stern DF. Polo-like Kinase 1 and Chk2 Interact and Co-localize to Centrosomes and the Midbody*. Journal Of Biological Chemistry 2002, 278: 8468-8475. PMID: 12493754, DOI: 10.1074/jbc.m211202200.Peer-Reviewed Original ResearchConceptsPhosphorylation of Chk2Polo-like kinase 1Thr-68DNA damageSimilar subcellular localization patternsDNA damage checkpoint pathwayKinase 1Damage checkpoint pathwaySubcellular localization patternsChromosome segregationMitotic exitLate mitosisNuclear fociMitotic entryIndirect immunofluorescence microscopyMitotic checkpointSer-28Early mitosisCheckpoint pathwayChk2Localization patternsCentrosomesThr-26Immunofluorescence microscopyMidbodyNFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways*
Xu X, Stern DF. NFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways*. Journal Of Biological Chemistry 2002, 278: 8795-8803. PMID: 12499369, DOI: 10.1074/jbc.m211392200.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid SequenceBase SequenceCell Cycle ProteinsChromatinDNA DamageDNA PrimersDNA ReplicationDNA-Binding ProteinsFluorescent Antibody Technique, IndirectG2 PhaseHeLa CellsHumansMitosisMolecular Sequence DataNuclear ProteinsPhosphorylationSequence Homology, Amino AcidSignal TransductionTrans-ActivatorsConceptsN-terminal FHA domainChromatin-associated proteinsDNA damageDNA Damage Signaling PathwayDNA double-strand breaksDiscrete nuclear fociDNA damage responseNumber of proteinsDouble-strand breaksBRCT domainFHA domainGamma-H2AX fociNuclear fociRad50 fociDamage responseDNA repairNFBD1Signaling pathwaysTandem repeatsProteinNuclear factorUntreated cellsHydroxyurea treatmentPathwayDiffuse nuclear stainingSpecificity within the EGF family/ErbB receptor family signaling network
Riese D, Stern D. Specificity within the EGF family/ErbB receptor family signaling network. BioEssays 1998, 20: 41-48. PMID: 9504046, DOI: 10.1002/(sici)1521-1878(199801)20:1<41::aid-bies7>3.0.co;2-v.Peer-Reviewed Original ResearchConceptsErbB family receptorsFamily receptorsEpidermal growth factor (EGF) familyErbB receptor familyGrowth factor familyPeptide growth factorsReceptor couplingHormone-receptor interactionBiological responsesGrowth factorHormoneMultiple receptorsReceptorsReceptor familyCell proliferationErbB familyMultiple hormonesReceptor partnersTyrosine kinaseDiverse biological responsesActivation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor.
DiGiovanna MP, Stern DF. Activation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor. Cancer Research 1995, 55: 1946-55. PMID: 7728765.Peer-Reviewed Original ResearchConceptsHuman breast tumorsBreast tumorsPrimary human breast tumorsPoor patient prognosisSubset of tumorsEpidermal growth factor receptorGrowth factor receptorPatient prognosisImmunohistochemical stainingNeu/ErbBTumor samplesTumorsMonoclonal antibodiesHuman tumorsFactor receptorRelated receptorsReceptorsP185Polyclonal antibodiesAntibodiesErbBRelated epidermal growth factor receptorSubsetTyrosine phosphoproteinsPrognosisThe Cellular Response to Neuregulins Is Governed by Complex Interactions of the erbB Receptor Family
Riese D, van Raaij T, Plowman G, Andrews G, Stern D. The Cellular Response to Neuregulins Is Governed by Complex Interactions of the erbB Receptor Family. Molecular And Cellular Biology 1995, 15: 5770-5776. PMID: 7565730, PMCID: PMC230829, DOI: 10.1128/mcb.15.10.5770.Peer-Reviewed Original ResearchConceptsReceptor familyEpidermal growth factor receptor tyrosine kinase familyErbB family receptorsErbB receptor familyReceptor tyrosine kinase familyReceptor tyrosine phosphorylationPeptide agonistsFamily receptorsTyrosine kinase familyHuman cancersReceptor interactionEpidermal growth factor homology domainsCell linesCell survivalReceptorsNeuregulinCellular responsesTyrosine phosphorylationAntiserum raised against a synthetic phosphotyrosine-containing peptide selectively recognizes p185neu/erbB-2 and the epidermal growth factor receptor.
Bangalore L, Tanner AJ, Laudano AP, Stern DF. Antiserum raised against a synthetic phosphotyrosine-containing peptide selectively recognizes p185neu/erbB-2 and the epidermal growth factor receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 1992, 89: 11637-11641. PMID: 1280833, PMCID: PMC50608, DOI: 10.1073/pnas.89.23.11637.Peer-Reviewed Original Research
2021
Identifying modules of cooperating cancer drivers
Klein MI, Cannataro VL, Townsend JP, Newman S, Stern DF, Zhao H. Identifying modules of cooperating cancer drivers. Molecular Systems Biology 2021, 17: msb20209810. PMID: 33769711, PMCID: PMC7995435, DOI: 10.15252/msb.20209810.Peer-Reviewed Original ResearchConceptsCancer typesNRAS-mutant melanomaCombination of alterationsMultiple cancer typesClinical outcomesNFE2L2 mutationsIndividual patientsDriver alterationsEffective personalized treatmentPathway inhibitionTherapeutic potentialCancer etiologyPersonalized treatmentTumor formationTCGA cancer typesAlterationsPatientsCancer driversEtiologyMelanomaCancer
2020
Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Gale M, Li Y, Cao J, Liu ZZ, Holmbeck MA, Zhang M, Lang SM, Wu L, Do Carmo M, Gupta S, Aoshima K, DiGiovanna MP, Stern DF, Rimm DL, Shadel GS, Chen X, Yan Q. Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition. Cancer Research 2020, 80: 524-535. PMID: 31690671, PMCID: PMC7002225, DOI: 10.1158/0008-5472.can-18-3985.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBreast NeoplasmsCell ProliferationDrug Resistance, NeoplasmEnzyme InhibitorsFemaleHumansMiceMice, Inbred NODMice, SCIDMitochondrial Proton-Translocating ATPasesOligomycinsReceptor, ErbB-2TrastuzumabTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsResistant cellsHER2-Targeted TherapyTrastuzumab-resistant tumorsNew therapeutic strategiesNovel potential targetDrug-free mediumAntibody therapySynthase inhibitionLow doseTherapeutic strategiesTrastuzumabBreast tumorsHER2TherapyAcquired ResistanceTumorsPotential targetMitochondrial respirationCellsSelective dependencyInhibitionMinimal changesNovel vulnerabilitiesATP synthase inhibitionOligomycin A
2018
Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer
Theodosakis N, Langdon CG, Micevic G, Krykbaeva I, Means RE, Stern DF, Bosenberg MW. Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer. Pigment Cell & Melanoma Research 2018, 32: 292-302. PMID: 30281931, PMCID: PMC6590911, DOI: 10.1111/pcmr.12742.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationColorectal NeoplasmsDrug Resistance, NeoplasmDrug SynergismHumansHydroxymethylglutaryl-CoA Reductase InhibitorsLung NeoplasmsMaleMelanomaMevalonic AcidMice, NudeMitogen-Activated Protein KinasesPrenylationProtein Kinase InhibitorsProtein Processing, Post-TranslationalSignal TransductionConceptsUseful adjunctive therapyHMG-CoA reductase inhibitorsAnti-tumor effectsAdjunctive therapyInhibition of isoprenylationLung cancerMEK inhibitionReductase inhibitorsMAPK blockadeDriver mutationsAdditional studiesStatinsTherapyMelanomaTumorsVemurafenibMAPK pathwayDownstream metabolitesInhibitionMAPKAdjunctiveColorectalSelumetinibBlockadeCancerKeeping Tumors Out of the MAPK Fitness Zone
Stern DF. Keeping Tumors Out of the MAPK Fitness Zone. Cancer Discovery 2018, 8: 20-23. PMID: 29311225, DOI: 10.1158/2159-8290.cd-17-1243.Peer-Reviewed Original ResearchConceptsMAPK-targeted therapiesGreater fitnessMAPK signalingTumor cell subclonesMAPK pathwayCell deathERK inhibitorDNA damageTumor cell deathFitness barriersCell subclonesNew therapeutic approachesInhibitor withdrawalResistant clonesTherapeutic approachesTriple combinationMEKSignalingClonesSubclonesFitnessPathwayPatients
2017
GRAPE: a pathway template method to characterize tissue-specific functionality from gene expression profiles
Klein MI, Stern DF, Zhao H. GRAPE: a pathway template method to characterize tissue-specific functionality from gene expression profiles. BMC Bioinformatics 2017, 18: 317. PMID: 28651562, PMCID: PMC5485588, DOI: 10.1186/s12859-017-1711-z.Peer-Reviewed Original ResearchConceptsGene expression profilesExpression profilesIndividual gene expression profilesTissue-specific functionalityEnrichment-based methodsPathway scoresGene expression levelsBatch effectsPathway genesPresent genesPerturbed pathwaysPathway expressionExpression levelsIndividual samplesTissue typesPathwayGenesTCGA subtypesAbnormal pathwaysIndependent datasetsBreast cancer subtypesNon-competitive approachIndividual tumorsCancer subtypesGrapesp90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis
Theodosakis N, Micevic G, Langdon CG, Ventura A, Means R, Stern DF, Bosenberg MW. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. Journal Of Investigative Dermatology 2017, 137: 2187-2196. PMID: 28599981, PMCID: PMC6342201, DOI: 10.1016/j.jid.2016.12.033.Peer-Reviewed Original ResearchConceptsProtein synthesisRibosomal S6 kinase (RSK) familyPatient-derived melanoma cell linesDifferential protein expressionReverse phase protein arrayPhase protein arrayTranslation complexesKinase familyBI-D1870RSK inhibitorsMelanoma cell linesProtein arraysCell proliferationInhibitor treatmentProtein expressionCell linesNew targetsHuman melanoma patientsBRAF inhibitor vemurafenibCombinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor
Langdon CG, Platt JT, Means RE, Iyidogan P, Mamillapalli R, Klein M, Held MA, Lee JW, Koo JS, Hatzis C, Hochster HS, Stern DF. Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor. Molecular Cancer Therapeutics 2017, 16: 1041-1053. PMID: 28292938, PMCID: PMC5457712, DOI: 10.1158/1535-7163.mct-16-0794.Peer-Reviewed Original ResearchAdenosine TriphosphateAnimalsAntineoplastic AgentsApoptosisCarcinoma, Pancreatic DuctalCell Line, TumorCell ProliferationDNA DamageDose-Response Relationship, DrugDrug CombinationsDrug Screening Assays, AntitumorDrug SynergismHigh-Throughput Nucleotide SequencingHumansMiceMitochondriaMolecular Targeted TherapyNeoplastic Stem CellsPancreatic NeoplasmsSuperoxidesXenograft Model Antitumor AssaysSystematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer
Wali VB, Langdon CG, Held MA, Platt JT, Patwardhan GA, Safonov A, Aktas B, Pusztai L, Stern DF, Hatzis C. Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer. Cancer Research 2017, 77: 566-578. PMID: 27872098, PMCID: PMC5582957, DOI: 10.1158/0008-5472.can-16-1901.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerTNBC cell linesPairwise drug combinationsClinical translationAggressive diseaseCombination therapyBreast cancerPreclinical proofDrug combinationsCombination treatmentInvestigational drugsSingle agentSensitivity patternCell sensitivityCell linesTherapyApoptotic activityAnticancer activityDownregulated genesMitogenic signalingCrizotinibBlockadeClinicAgentsCancerA Computational Approach for Identifying Synergistic Drug Combinations
Gayvert KM, Aly O, Platt J, Bosenberg MW, Stern DF, Elemento O. A Computational Approach for Identifying Synergistic Drug Combinations. PLOS Computational Biology 2017, 13: e1005308. PMID: 28085880, PMCID: PMC5234777, DOI: 10.1371/journal.pcbi.1005308.Peer-Reviewed Original Research
2016
Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival – Evidence from TCGA Pan-Cancer Data
Huang X, Stern DF, Zhao H. Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival – Evidence from TCGA Pan-Cancer Data. Scientific Reports 2016, 6: 20567. PMID: 26837275, PMCID: PMC4738355, DOI: 10.1038/srep20567.Peer-Reviewed Original ResearchConceptsPatient survivalTumor cell contaminationField cancerization effectNormal samplesCancer patient survivalNormal tissue samplesSitu immunizationCancer Genome AtlasCancer patientsPatient progressionNormal controlsTumorsNormal tissuesPan-cancer dataTissue samplesGenome AtlasCancer studiesDisease etiologyCell contaminationPatientsPathway analysisTCGA pan-cancer dataSurvivalTranscriptional profilesPotential benefits