Featured Publications
Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
Adua S, Arnal-Estapé A, Zhao M, Qi B, Liu Z, Kravitz C, Hulme H, Strittmatter N, López-Giráldez F, Chande S, Albert A, Melnick M, Hu B, Politi K, Chiang V, Colclough N, Goodwin R, Cross D, Smith P, Nguyen D. Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer. Nature Communications 2022, 13: 7690. PMID: 36509758, PMCID: PMC9744876, DOI: 10.1038/s41467-022-34889-z.Peer-Reviewed Original ResearchConceptsGene expression programsRas homolog family member ACancer cellsFamily member AEpidermal growth factor receptorExpression programsMetastatic cancer cellsSRF signalingGrowth factor receptorTumor microenvironmentLung cancerFunctional linkExtracellular lamininDrug-resistant cancer cellsMutant non-small cell lung cancerNon-small cell lung cancerCentral nervous system relapseMolecular studiesMember AEGFR-mutant lung cancerFactor receptorNervous system relapseCell lung cancerDisseminated tumor cellsBrain tumor microenvironmentTranscriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis
Wingrove E, Liu ZZ, Patel KD, Arnal-Estapé A, Cai WL, Melnick MA, Politi K, Monteiro C, Zhu L, Valiente M, Kluger HM, Chiang VL, Nguyen DX. Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis. Cell Reports 2019, 27: 1277-1292.e7. PMID: 31018140, PMCID: PMC6592283, DOI: 10.1016/j.celrep.2019.03.085.Peer-Reviewed Original ResearchConceptsBrain metastasesBrain tumor microenvironmentLineage programTumor microenvironmentTumor plasticityStromal gene expressionTranscriptomic hallmarksGene expressionTranscriptional hallmarksMultiple tumor typesMolecular landscapeStromal interactionsMajor siteIntact tissueNeuroinflammatory responseSyngeneic modelPatient biopsiesTumor typesMetastasisMalignant cellsDifferent subtypesTumor cellsHallmarkTranscriptomeCellsTumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6
Arnal-Estapé A, Cai WL, Albert AE, Zhao M, Stevens LE, López-Giráldez F, Patel KD, Tyagi S, Schmitt EM, Westbrook TF, Nguyen DX. Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6. Oncogene 2020, 39: 3726-3737. PMID: 32157212, PMCID: PMC7190573, DOI: 10.1038/s41388-020-1246-z.Peer-Reviewed Original ResearchConceptsChromatin landscapeTranscription factorsBone morphogenetic protein (BMP) signalingDiverse transcriptional programsAlters chromatin accessibilityMultiple genomic lociMorphogenetic protein signalingDistal enhancer elementsSelective transcription factorsEpithelial cell typesSurfactant protein CChromatin accessibilityGenomic lociTranscriptional programsLung adenocarcinoma progressionTumor progressionEpigenetic mechanismsProtein signalingBiological functionsLUAD progressionLUAD cellsEnhancer elementsLineage dependencyTumor suppressionLung cancer cellsHuman WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation
Cai WL, Chen JF, Chen H, Wingrove E, Kurley SJ, Chan LH, Zhang M, Arnal-Estape A, Zhao M, Balabaki A, Li W, Yu X, Krop ED, Dou Y, Liu Y, Jin J, Westbrook TF, Nguyen DX, Yan Q. Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation. ELife 2022, 11: e78163. PMID: 36043466, PMCID: PMC9584608, DOI: 10.7554/elife.78163.Peer-Reviewed Original ResearchConceptsBreast cancer cellsMetastatic breast cancerBreast cancerRibosomal gene expressionCancer cellsKnockdown of WDR5Vivo genetic screenReversible epigenetic mechanismsGenetic screenTranslation regulationTriple-negative breast cancerEpigenetic regulatorsEpigenetic mechanismsBreast cancer growthCancer-related deathTranslation efficiencyWDR5Novel therapeutic strategiesTranslation rateGene expressionCell growthAdvanced diseaseEffective therapyMetastatic capabilityPotent suppressionPreclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs
Colclough N, Chen K, Johnström P, Strittmatter N, Yan Y, Wrigley GL, Schou M, Goodwin R, Varnäs K, Adua SJ, Zhao M, Nguyen DX, Maglennon G, Barton P, Atkinson J, Zhang L, Janefeldt A, Wilson J, Smith A, Takano A, Arakawa R, Kondrashov M, Malmquist J, Revunov E, Vazquez-Romero A, Moein MM, Windhorst AD, Karp NA, Finlay MRV, Ward RA, Yates JWT, Smith PD, Farde L, Cheng Z, Cross DAE. Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs. Clinical Cancer Research 2021, 27: 189-201. PMID: 33028591, DOI: 10.1158/1078-0432.ccr-19-1871.Peer-Reviewed Original ResearchConceptsBlood-brain barrier permeabilityBrain metastasesBrain penetranceBarrier permeabilityEGFR tyrosine kinase inhibitorsT790M resistance mutationMetastatic brain diseaseSubclinical brain metastasesSelective EGFR tyrosine kinase inhibitorOngoing clinical evaluationM resistance mutationTyrosine kinase inhibitorsBBB penetranceBrain tumor growthClinical efficacyEGFR-TKIEGFR-TKIsBrain penetrationClinical evaluationPreclinical comparisonPreclinical modelsPreclinical studiesCynomolgus macaquesOsimertinibTumor growthControl of Alveolar Differentiation by the Lineage Transcription Factors GATA6 and HOPX Inhibits Lung Adenocarcinoma Metastasis
Cheung WK, Zhao M, Liu Z, Stevens LE, Cao PD, Fang JE, Westbrook TF, Nguyen DX. Control of Alveolar Differentiation by the Lineage Transcription Factors GATA6 and HOPX Inhibits Lung Adenocarcinoma Metastasis. Cancer Cell 2013, 23: 725-738. PMID: 23707782, PMCID: PMC3697763, DOI: 10.1016/j.ccr.2013.04.009.Peer-Reviewed Original ResearchConceptsTranscription factor GATA6Normal cell differentiationAlveolar differentiationTumor cell survivalTranscriptional programsLung adenocarcinoma progressionMolecular programsEpithelial specificationTarget genesAirway epithelial differentiationCell differentiationMetastatic competenceCell survivalLung adenocarcinoma metastasisInhibition of metastasisGATA6Adenocarcinoma progressionEpithelial differentiationDifferentiationGenesHOPXADC subtypesAdenocarcinoma metastasisLung cancerADC cells
2023
Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
de Miguel F, Gentile C, Feng W, Silva S, Sankar A, Exposito F, Cai W, Melnick M, Robles-Oteiza C, Hinkley M, Tsai J, Hartley A, Wei J, Wurtz A, Li F, Toki M, Rimm D, Homer R, Wilen C, Xiao A, Qi J, Yan Q, Nguyen D, Jänne P, Kadoch C, Politi K. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 2023, 41: 1516-1534.e9. PMID: 37541244, PMCID: PMC10957226, DOI: 10.1016/j.ccell.2023.07.005.Peer-Reviewed Original ResearchConceptsMammalian SWI/SNF chromatinSWI/SNF chromatinMSWI/SNF complexesGenome-wide localizationGene regulatory signaturesNon-genetic mechanismsEpithelial cell differentiationEGFR-mutant cellsChromatin accessibilitySNF complexCellular programsRegulatory signaturesTKI-resistant lung cancerGene targetsKinase inhibitor resistanceCell differentiationMesenchymal transitionTKI resistancePharmacologic disruptionTyrosine kinase inhibitor resistanceCell proliferationChromatinInhibitor resistanceEGFR-mutant lungKinase inhibitorsEpigenetic markers and therapeutic targets for metastasis
Kravitz C, Yan Q, Nguyen D. Epigenetic markers and therapeutic targets for metastasis. Cancer And Metastasis Reviews 2023, 42: 427-443. PMID: 37286865, PMCID: PMC10595046, DOI: 10.1007/s10555-023-10109-y.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsEpigenomic alterationsLineage integrityTherapeutic targetEpigenetic markersCancer cellsGenetic aberrationsCurrent knowledgeHuman tumorsMalignant cell cloneTumor progressionDNANumber of discoveriesCell clonesDisseminated diseaseCertain organsPrimary tumorTherapeutic responseMetastatic cancerEpigenomeChromatinHistonesLiquid biopsyAlterationsClonesTarget
2021
Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF
Cheok SK, Narayan A, Arnal-Estape A, Gettinger S, Goldberg SB, Kluger HM, Nguyen D, Patel A, Chiang V. Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF. JCO Precision Oncology 2021, 5: 163-172. PMID: 34250381, PMCID: PMC8232069, DOI: 10.1200/po.20.00292.Peer-Reviewed Original ResearchConceptsIntraparenchymal brain metastasesBrain metastasesCell-free DNAExtracranial tumorsBrain metastasis tissuesProgressive brain metastasesThird of patientsNormal pressure hydrocephalusTumor DNA mutationsPrimary cancer typeAnalysis of CSFSamples of CSFLeptomeningeal diseaseEffective surrogate markerBrain biopsyPressure hydrocephalusLumbar punctureSurrogate markerCancer-associated genesMetastasis tissuesPatientsMetastasisDiscordant responsesRenal cellsGenomic profiling
2020
Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain
Cai WL, Greer CB, Chen JF, Arnal-Estapé A, Cao J, Yan Q, Nguyen DX. Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain. BMC Medical Genomics 2020, 13: 33. PMID: 32143622, PMCID: PMC7060551, DOI: 10.1186/s12920-020-0695-0.Peer-Reviewed Original ResearchConceptsOpen chromatin signaturesTranscription factorsChromatin landscapeChromosome conformation captureOpen chromatin landscapeSpecific chromatin landscapesHomophilic cell adhesionTransposase-accessible chromatinEnhancer-promoter interactionsSpecific transcription factorsActive chromatin sitesATAC-seq dataMetastatic cellsGene expression dataChromatin signaturesConformation captureChromatin sitesActive chromatinATAC-seqEpigenomic propertiesChIP-seqChromatin immunoprecipitationEndothelial cell migrationEpigenomic analysisTranscriptomic differences
2017
Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases
Stevens LE, Cheung WKC, Adua SJ, Arnal-Estapé A, Zhao M, Liu Z, Brewer K, Herbst RS, Nguyen DX. Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases. Cancer Research 2017, 77: 1905-1917. PMID: 28196904, PMCID: PMC5468792, DOI: 10.1158/0008-5472.can-16-1978.Peer-Reviewed Original ResearchConceptsBrain metastatic nicheRisk of relapseDistant metastasisPoor prognosisLUAD subtypesLung tumorsLung adenocarcinomaLUAD cellsMetastatic outgrowthMetastatic nicheCancer ResCancer cellsECM-mediated signalingExtracellular matrix moleculesCell survivalMolecular signaturesDifferential expressionHMMRMatrix moleculesImportant mechanismCellsRelapseAdenocarcinomaPrognosisMetastasis