2023
Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma
Chaudhary P, Xu X, Wang G, Hoj J, Rampersad R, Asselin-Labat M, Ting S, Kim W, Tamayo P, Pendergast A, Onaitis M. Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma. Cancer Research Communications 2023, 3: 2400-2411. PMID: 37882674, PMCID: PMC10668634, DOI: 10.1158/2767-9764.crc-22-0408.Peer-Reviewed Original ResearchConceptsType II cellsLung adenocarcinomaDual-positive cellsII cellsKRAS-mutant lung adenocarcinomaDevelopment of novel targeted therapeuticsTumor-initiating cellsNotch signalingAlveolar type II cellsNovel targeted therapeuticsCell of originThree-dimensional organoid culturesSOX2 upregulationKRAS activationAdenocarcinomaMouse modelTherapeutic strategiesProliferation of cellsGain-of-functionRNA sequencing analysisTransplantation studiesCellular plasticityOrganoid culturesSOX2 levelsNotch pathway
2022
MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer
Yoshida R, Saigi M, Tani T, Springer B, Shibata H, Kitajima S, Mahadevan N, Campisi M, Kim W, Kobayashi Y, Thai T, Haratani K, Yamamoto Y, Sundararaman S, Knelson E, Vajdi A, Canadas I, Uppaluri R, Paweletz C, Miret J, Lizotte P, Gokhale P, Jänne P, Barbie D. MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer. Cancer Research 2022, 82: 4079-4092. PMID: 36066413, PMCID: PMC9627131, DOI: 10.1158/0008-5472.can-22-0770.Peer-Reviewed Original ResearchConceptsEGFR-mutant lung cancerEGFR-TKI-resistant cellsThird-generation EGFR tyrosine kinase inhibitorMET-amplifiedT cell responsesPemetrexed treatmentLung cancerCD8+ T cell immunogenicityEGFR-TKI treatment failureEGFR tyrosine kinase inhibitorsInhibit T cell responsesUpregulation of CD73Humanized mouse modelTyrosine kinase inhibitorsT-cell immunogenicityCell line studiesMET amplificationEGFR-TKIsTKI resistanceTreatment failureCancer immunogenicityCD73 inhibitionT cellsPemetrexedEnhanced immunogenicityCHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Bernareggi D, Xie Q, Prager B, Yun J, Cruz L, Pham T, Kim W, Lee X, Coffey M, Zalfa C, Azmoon P, Zhu H, Tamayo P, Rich J, Kaufman D. CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity. Nature Communications 2022, 13: 1899. PMID: 35393416, PMCID: PMC8990014, DOI: 10.1038/s41467-022-29469-0.Peer-Reviewed Original ResearchConceptsResistance to NK cell-mediated cytotoxicityHead and neck squamous cell carcinomaNK cell-mediated killingNK cell-mediated cytotoxicityCell-mediated cytotoxicityCell-mediated killingTumor cellsGlioblastoma stem cellsNatural killerNK cellsIncreased NK cell-mediated killingMechanism of tumor immune escapeHead and neck squamous cell carcinoma modelResistance to NK cellsNeck squamous cell carcinomaApoptosis of NK cellsNK cell-mediated immunotherapyExtracellular vesiclesCell-mediated immunotherapyTumor immune escapeImmunodeficient mouse modelSquamous cell carcinomaNK cell migrationIncreased chemokine secretionHuman glioblastoma stem cells
2020
Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation
Liu C, Sadat S, Ebisumoto K, Sakai A, Panuganti B, Ren S, Goto Y, Haft S, Fukusumi T, Ando M, Saito Y, Guo T, Tamayo P, Yeerna H, Kim W, Hubbard J, Sharabi A, Gutkind J, Califano J. Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation. Clinical Cancer Research 2020, 26: 2693-2703. PMID: 31932491, PMCID: PMC7538010, DOI: 10.1158/1078-0432.ccr-18-3301.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCannabinoidsCell MovementCell ProliferationFemaleHead and Neck NeoplasmsHumansMiceMice, NudeP38 Mitogen-Activated Protein KinasesPapillomaviridaePapillomavirus InfectionsPrognosisReceptors, CannabinoidSquamous Cell Carcinoma of Head and NeckTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsHead and neck squamous cell carcinomaHPV-positive head and neck squamous cell carcinomaHPV-positive HNSCC cell linesNeck squamous cell carcinomaHNSCC cell linesSingle-sample gene set enrichment analysisSquamous cell carcinomaP38 MAPK pathway activationHNSCC cohortCell carcinomaMAPK pathway activationHPV-negative head and neck squamous cell carcinomaHuman papillomavirus (HPV)-related headCell linesAnimal modelsCannabinoid receptor activationHPV- HNSCC patientsHead and neck squamous cell carcinomas dataMarijuana usePathway activationDaily marijuana useWhole-genome expression analysisCannabinoid exposureHNSCC patientsP38 MAPK activationSTRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells
Kim J, Berrios C, Kim M, Schade A, Adelmant G, Yeerna H, Damato E, Iniguez A, Florens L, Washburn M, Stegmaier K, Gray N, Tamayo P, Gjoerup O, Marto J, DeCaprio J, Hahn W. STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells. ELife 2020, 9: e53003. PMID: 31913126, PMCID: PMC6984821, DOI: 10.7554/elife.53003.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCalmodulin-Binding ProteinsCell ProliferationCell Transformation, NeoplasticFemaleGene Knockdown TechniquesHEK293 CellsHeterograftsHumansIntracellular Signaling Peptides and ProteinsMicePhosphoprotein PhosphatasesProtein Serine-Threonine KinasesSignal TransductionTranscription FactorsYAP-Signaling ProteinsConceptsStriatin-interacting phosphatase and kinaseSV40 small t antigenB subunitCell transformationPP2A subunitsHippo pathway effector YAP1Regulatory B subunitPP2A B subunitsPP2A-mediated dephosphorylationSmall t antigenInduce cell transformationPP2A functionPP2A complexPP2A activityOncogenic transformationSubunit interactionsPP2AHuman cancersT antigenMAP4K4SubunitAssociated with STCell alterationsPartial lossCells
2018
Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS
Kitajima S, Asahina H, Chen T, Guo S, Quiceno L, Cavanaugh J, Merlino A, Tange S, Terai H, Kim J, Wang X, Zhou S, Xu M, Wang S, Zhu Z, Thai T, Takahashi C, Wang Y, Neve R, Stinson S, Tamayo P, Watanabe H, Kirschmeier P, Wong K, Barbie D. Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS. Cancer Cell 2018, 34: 439-452.e6. PMID: 30205046, PMCID: PMC6422029, DOI: 10.1016/j.ccell.2018.08.009.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsAntineoplastic Agents, ImmunologicalCarcinoma, Non-Small-Cell LungCell Line, TumorDisease Models, AnimalDrug Resistance, NeoplasmHEK293 CellsHumansImmunity, InnateInsulin-Like Growth Factor ILung NeoplasmsMiceMice, TransgenicMitogen-Activated Protein Kinase KinasesPhosphoproteinsProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)Transcription FactorsYAP-Signaling ProteinsConceptsGenetically engineered mouse modelsMediators of acquired resistanceDownstream of KRASBET inhibitor JQ1Effective therapeutic strategyTumor shrinkageTargeted therapyIntermittent treatmentYAP1 signalingMouse modelPathway inhibitionBET inhibitionTherapeutic strategiesInhibitor JQ1YAP1 upregulationOncogenic KRASBET inhibitorsOvercome resistancePromoter acetylationIntrinsic resistancePotential translationKRASMEKInnateInhibitionEx Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids
Jenkins R, Aref A, Lizotte P, Ivanova E, Stinson S, Zhou C, Bowden M, Deng J, Liu H, Miao D, He M, Walker W, Zhang G, Tian T, Cheng C, Wei Z, Palakurthi S, Bittinger M, Vitzthum H, Kim J, Merlino A, Quinn M, Venkataramani C, Kaplan J, Portell A, Gokhale P, Phillips B, Smart A, Rotem A, Jones R, Keogh L, Anguiano M, Stapleton L, Jia Z, Barzily-Rokni M, Cañadas I, Thai T, Hammond M, Vlahos R, Wang E, Zhang H, Li S, Hanna G, Huang W, Hoang M, Piris A, Eliane J, Stemmer-Rachamimov A, Cameron L, Su M, Shah P, Izar B, Thakuria M, LeBoeuf N, Rabinowits G, Gunda V, Parangi S, Cleary J, Miller B, Kitajima S, Thummalapalli R, Miao B, Barbie T, Sivathanu V, Wong J, Richards W, Bueno R, Yoon C, Miret J, Herlyn M, Garraway L, Van Allen E, Freeman G, Kirschmeier P, Lorch J, Ott P, Hodi F, Flaherty K, Kamm R, Boland G, Wong K, Dornan D, Paweletz C, Barbie D. Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discovery 2018, 8: cd-17-0833. PMID: 29101162, PMCID: PMC5809290, DOI: 10.1158/2159-8290.cd-17-0833.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, ImmunologicalCell Culture TechniquesCell Line, TumorCytokinesDrug Resistance, NeoplasmFlow CytometryHumansImmunohistochemistryImmunophenotypingMiceMicrofluidic Analytical TechniquesProgrammed Cell Death 1 ReceptorSpheroids, CellularTime-Lapse ImagingTumor Cells, CulturedConceptsImmune checkpoint blockadePD-1 blockadeResistance to PD-1 blockadeDevelopment of effective combination therapiesResistance to immune checkpoint blockadeResponse to ICBResponse to immune checkpoint blockadeImmunocompetent mouse tumor modelsTumor immune microenvironmentPrecision immuno-oncologyMyeloid cell populationsEffective combination therapyMouse tumor modelsProfile of secreted cytokinesEx vivo profileCheckpoint blockadePD-1Combination therapyImmune microenvironmentImmuno-oncologyTherapeutic combinationsTumor microenvironmentMurine modelTumor modelPatient specimens
2017
Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations
Huang F, Mosquera J, Garofalo A, Oh C, Baco M, Amin-Mansour A, Rabasha B, Bahl S, Mullane S, Robinson B, Aldubayan S, Khani F, Karir B, Kim E, Chimene-Weiss J, Hofree M, Romanel A, Osborne J, Kim J, Azabdaftari G, Woloszynska-Read A, Sfanos K, De Marzo A, Demichelis F, Gabriel S, Van Allen E, Mesirov J, Tamayo P, Rubin M, Powell I, Garraway L. Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations. Cancer Discovery 2017, 7: 973-983. PMID: 28515055, PMCID: PMC5836784, DOI: 10.1158/2159-8290.cd-16-0960.Peer-Reviewed Original ResearchConceptsProstate cancerRecurrent loss-of-function mutationsSystematic genome sequencingCastration-resistant prostate cancerLethal castration-resistant prostate cancerProstate cancer tumor suppressor geneCancer sequencing studiesCancer genome characterizationLoss-of-function mutationsIncreased anchorage-independent growthPrimary prostate cancerAfrican American menProstate cancer cohortAnchorage-independent growthTumor suppressor geneProstate cancer genesGene expression signaturesTranscriptional repressorGenomic characterizationSequencing studiesExome sequencingCancer genesAndrogen signalingGene mutationsCancer cohort
2016
DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets
Hanaford A, Archer T, Price A, Kahlert U, Maciaczyk J, Nikkhah G, Kim J, Ehrenberger T, Clemons P, Dančík V, Seashore-Ludlow B, Viswanathan V, Stewart M, Rees M, Shamji A, Schreiber S, Fraenkel E, Pomeroy S, Mesirov J, Tamayo P, Eberhart C, Raabe E. DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets. Clinical Cancer Research 2016, 22: 3903-3914. PMID: 27012813, PMCID: PMC5055054, DOI: 10.1158/1078-0432.ccr-15-3011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBiomarkersCell Line, TumorCerebellar NeoplasmsComputational BiologyComputer SimulationCyclin-Dependent KinasesDisease Models, AnimalDrug DiscoveryGene Expression ProfilingGenetic Predisposition to DiseaseHumansMedulloblastomaMiceModels, BiologicalNeural Stem CellsPhosphorylationPiperazinesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-mycPyridinesTranscriptomeTumor Suppressor Protein p53Xenograft Model Antitumor AssaysConceptsGroup 3 medulloblastomaProgenitor cellsHuman neural stemCyclin-dependent kinasesRare tumorHuman neural stem cell modelNeural stemGenetically accurate modelsSurvival of miceDominant-negative p53Stem cell modelPotential effective treatmentConstitutively active AktAggressive medulloblastomaDrug sensitivity datasetsDrug sensitivity databaseNovel therapeutic targetsMedulloblastoma xenograftsAccurate disease modelsHuman stemInnovative therapiesIncreased apoptosisNeural stem cell modelIn silico analysisIn silico analysis methods
2015
KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine
Stewart M, Tamayo P, Wilson A, Wang S, Chang Y, Kim J, Khabele D, Shamji A, Schreiber S. KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine. Cancer Research 2015, 75: 2897-2906. PMID: 25968887, PMCID: PMC4506246, DOI: 10.1158/0008-5472.can-14-2860.Peer-Reviewed Original ResearchConceptsOvarian cancer cellsCancer cellsOvarian cancerHigh-grade serous ovarian cancer cellsGenomic statusBiomarkers of drug responseBcl-2 family inhibitorsAntitumor response rateSerous ovarian cancer cellsTreated with decitabineInhibit DNA methylationBreast cancer cellsDownregulation of DNMT1DNA methyltransferase inhibitionKRAS statusDNA methylationPredictive biomarkersSolid tumorsMEK inhibitorsMEK/ERK phosphorylationDecitabineBcl-2Drug responseXenograft modelLow-grade
2014
KRAS and YAP1 Converge to Regulate EMT and Tumor Survival
Shao D, Xue W, Krall E, Bhutkar A, Piccioni F, Wang X, Schinzel A, Sood S, Rosenbluh J, Kim J, Zwang Y, Roberts T, Root D, Jacks T, Hahn W. KRAS and YAP1 Converge to Regulate EMT and Tumor Survival. Cell 2014, 158: 171-184. PMID: 24954536, PMCID: PMC4110062, DOI: 10.1016/j.cell.2014.06.004.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCell Cycle ProteinsCell SurvivalColonic NeoplasmsDrug Delivery SystemsDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionHCT116 CellsHumansLung NeoplasmsMicePhosphoproteinsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)Ras ProteinsSignal TransductionTranscription FactorsTranscriptional ActivationYAP-Signaling ProteinsConceptsEpithelial-mesenchymal transitionTranscriptional regulator of epithelial-mesenchymal transitionOncogenic Ras signalingColon cancer cell linesTranscriptional coactivator YAP1KRAS-dependent cellsRegulator of epithelial-mesenchymal transitionMurine lung cancer modelTranscriptional regulationCancer cell linesMutant allelesRas signalingTranscription factor FosOncogenic RasTranscriptional programsLung cancer modelRegulating epithelial-mesenchymal transitionMolecular basisOncogenic alleleCell transformationYAP1YAP1 signalingPromote survivalCancer cellsOncogenic dependency