2024
Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB
Lampson B, Ramίrez A, Baro M, He L, Hegde M, Koduri V, Pfaff J, Hanna R, Kowal J, Shirole N, He Y, Doench J, Contessa J, Locher K, Kaelin W. Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB. Cell 2024, 187: 2209-2223.e16. PMID: 38670073, PMCID: PMC11149550, DOI: 10.1016/j.cell.2024.03.022.Peer-Reviewed Original ResearchConceptsWhole-genome CRISPR-Cas9 screenCRISPR-Cas9 screensCryoelectron microscopy studiesCell surface localizationLipopolysaccharide receptor Toll-like receptor 4OST complexToll-like receptor 4CRISPR screensNF-kBCatalytic subunitN-glycosylationActivate NF-kBBase editorsUncompetitive inhibition mechanismNGI-1Molecular mechanismsCatalytic siteLPS-treated cellsOligosaccharyltransferaseDruggable pocketSTT3AReceptor Toll-like receptor 4Drug mechanism of actionStructural studiesInflammatory signaling
2023
Signal recognition particle receptor-β (SR-β) coordinates cotranslational N-glycosylation
Phoomak C, Rinis N, Baro M, Shrimal S, Bennett D, Shaffer S, Lehrman M, Gilmore R, Contessa J. Signal recognition particle receptor-β (SR-β) coordinates cotranslational N-glycosylation. Science Advances 2023, 9: eade8079. PMID: 36921042, PMCID: PMC10017033, DOI: 10.1126/sciadv.ade8079.Peer-Reviewed Original ResearchConceptsSignal recognition particle receptorN-glycosylationProper protein foldingCotranslational N-glycosylationOligosaccharyltransferase complexPosttranslational modificationsProtein foldingSecretory compartmentsHigh-throughput screeningEndoplasmic reticulumCellular localizationUnrecognized functionChemical probesProteinTransloconReceptorsSubunitsFoldingReticulumMutationsPhenotypeCompartmentsAssemblyCellsLocalization
2021
STING enhances cell death through regulation of reactive oxygen species and DNA damage
Hayman TJ, Baro M, MacNeil T, Phoomak C, Aung TN, Cui W, Leach K, Iyer R, Challa S, Sandoval-Schaefer T, Burtness BA, Rimm DL, Contessa JN. STING enhances cell death through regulation of reactive oxygen species and DNA damage. Nature Communications 2021, 12: 2327. PMID: 33875663, PMCID: PMC8055995, DOI: 10.1038/s41467-021-22572-8.Peer-Reviewed Original Research
2019
Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma
Baro M, Lopez Sambrooks C, Burtness BA, Lemmon MA, Contessa JN. Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma. Molecular Cancer Therapeutics 2019, 18: 2124-2134. PMID: 31387891, PMCID: PMC6825559, DOI: 10.1158/1535-7163.mct-19-0163.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalCell Line, TumorCell ProliferationCell SurvivalCetuximabDrug Resistance, NeoplasmFemaleHead and Neck NeoplasmsHumansMiceNeuregulinsProto-Oncogene Proteins c-aktReceptor, ErbB-3Signal TransductionSquamous Cell Carcinoma of Head and NeckUp-RegulationXenograft Model Antitumor AssaysConceptsNeck squamous cell carcinomaSquamous cell carcinomaTherapeutic resistanceCell carcinomaResistant cellsConcentrations of cetuximabEFM-19 cellsCetuximab-resistant cellsActionable therapeutic targetsHNSCC cell linesTumor growth experimentsInhibition of EGFRErbB3 antibodyNeuregulin expressionOverall survivalTreatment regimensCetuximab resistanceTherapeutic targetAutocrine loopLocal controlTumor growthRadiotherapyEGFR inhibitionCetuximabNeuregulin SignalingOligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity
Baro M, Sambrooks C, Quijano A, Saltzman WM, Contessa J. Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity. Clinical Cancer Research 2019, 25: 784-795. PMID: 29967251, PMCID: PMC6314911, DOI: 10.1158/1078-0432.ccr-18-0792.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Cycle CheckpointsCell Line, TumorCell SurvivalDisease Models, AnimalDose-Response Relationship, DrugDose-Response Relationship, RadiationErbB ReceptorsGliomaHexosyltransferasesHumansMembrane ProteinsMiceRadiation ToleranceRadiation-Sensitizing AgentsReceptor Protein-Tyrosine KinasesSignal TransductionXenograft Model Antitumor AssaysConceptsNGI-1Cell cycle arrestDNA damageReceptor tyrosine kinase activationTyrosine kinase activationReceptor tyrosine kinasesSmall molecule inhibitorsEGFR family receptorsRTK signalingRTK activationXenograft tumor growthGlycosylation stateKinase activationTumor cell radiosensitivityExpression profilesProtein NTyrosine kinaseGlioma radiosensitivityParallel signalingTumor growthFamily activationCellular radiosensitivityFamily receptorsMechanistic roleProtein levels
2018
Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors
Lopez Sambrooks C, Baro M, Quijano A, Narayan A, Cui W, Greninger P, Egan R, Patel A, Benes CH, Saltzman WM, Contessa JN. Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors. Cancer Research 2018, 78: canres.0505.2018. PMID: 30026325, PMCID: PMC6125176, DOI: 10.1158/0008-5472.can-18-0505.Peer-Reviewed Original ResearchConceptsMutant NSCLCMutant non-small cell lung cancerNon-small cell lung cancerSignificant tumor growth delayEGFR-TKI treatmentCell lung cancerTyrosine kinase inhibitor resistanceEGFR tyrosine kinase inhibitor resistanceLung cancer cell linesNGI-1Tumor growth delayEffective therapeutic targetCell linesKinase inhibitor resistanceTumor cell viabilityH1975 xenograftsCancer cell linesTKI treatmentComplex transmembrane proteinsEGFR-TKILung cancerTumor responseCell cycle arrestPreclinical modelsTherapeutic strategies
2014
Dasatinib worsens the effect of cetuximab in combination with fractionated radiotherapy in FaDu- and A431-derived xenografted tumours
Baro M, de Llobet L, Figueras A, Skvortsova I, Mesia R, Balart J. Dasatinib worsens the effect of cetuximab in combination with fractionated radiotherapy in FaDu- and A431-derived xenografted tumours. British Journal Of Cancer 2014, 111: 1310-1318. PMID: 25077442, PMCID: PMC4183853, DOI: 10.1038/bjc.2014.432.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCell ProliferationCetuximabDasatinibDNA ReplicationDose Fractionation, RadiationFemaleHumansMiceMice, NudeNeovascularization, PathologicPyrimidinesRas ProteinsSrc-Family KinasesThiazolesTumor BurdenVascular Endothelial Growth Factor AXenograft Model Antitumor AssaysSimvastatin Enhances the Effects of Radiotherapy and Cetuximab on a Cell Line (FaDu) Derived from a Squamous Cell Carcinoma of Head and Neck
de Llobet L, Baro M, Mesia R, Balart J. Simvastatin Enhances the Effects of Radiotherapy and Cetuximab on a Cell Line (FaDu) Derived from a Squamous Cell Carcinoma of Head and Neck. Translational Oncology 2014, 7: 513-522. PMID: 25171892, PMCID: PMC4202798, DOI: 10.1016/j.tranon.2014.02.008.Peer-Reviewed Original ResearchEpidermal growth factor receptorExtracellular signal-regulated kinases 1Signal-regulated kinases 1Cell linesEfficient epidermal growth factor receptorPhosphorylated extracellular signal-regulated kinases 1Growth factor receptorA431 cell lineSignal transducerKinase BKinase 1Cancer progressionSynthesis of cholesterolFactor receptorCaspase-3Cell proliferationFaDu cellsCell culturesStatin simvastatinClonogenic assayTumor growthWound healingIsoprenoidsOncoproteinApoptosis
2012
Development and refinement of a technique using a medical radiation therapy facility to irradiate immunodeficient mice bearing xenografted human tumours
Baro M, de Llobet L, Modolell I, Guedea F, Visa J, Balart J. Development and refinement of a technique using a medical radiation therapy facility to irradiate immunodeficient mice bearing xenografted human tumours. Laboratory Animals 2012, 46: 345-348. PMID: 22723647, DOI: 10.1258/la.2012.011147.Peer-Reviewed Original ResearchDevelopment and characterization of an isogenic cell line with a radioresistant phenotype
de Llobet L, Baro M, Figueras A, Modolell I, Da Silva M, Muñoz P, Navarro A, Mesia R, Balart J. Development and characterization of an isogenic cell line with a radioresistant phenotype. Clinical And Translational Oncology 2012, 15: 189-197. PMID: 22855182, DOI: 10.1007/s12094-012-0898-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBlotting, WesternCarcinoma, Squamous CellCell CycleCell MovementCell ProliferationDose-Response Relationship, RadiationFemaleFlow CytometryGamma RaysHumansHyaluronan ReceptorsMiceMice, NudePhenotypeRadiation ToleranceTumor Cells, CulturedVascular Endothelial Growth Factor AWound HealingXenograft Model Antitumor AssaysConceptsCell linesIsogenic cancer cell linesIsogenic cell linesRadiation-induced DNA fragmentationCancer cellsSpecific cell functionsDNA repair abilityBiological traitsAppropriate study modelsCell cycle distributionVascular endothelial growth factor (VEGF) secretionMolecular characterizationCell survivalDNA fragmentationRadioresistant phenotypeCell growthCancer cell linesSecretion of VEGFGrowth factor secretionSingle cellsCycle distributionCell functionRepair abilityRadiation resistanceWestern blot
2011
The use of caspase inhibitors in pulsed-field gel electrophoresis may improve the estimation of radiation-induced DNA repair and apoptosis
Balart J, Pueyo G, de Llobet L, Baro M, Sole X, Marin S, Casanovas O, Mesia R, Capella G. The use of caspase inhibitors in pulsed-field gel electrophoresis may improve the estimation of radiation-induced DNA repair and apoptosis. Radiation Oncology 2011, 6: 6. PMID: 21235815, PMCID: PMC3025872, DOI: 10.1186/1748-717x-6-6.Peer-Reviewed Original ResearchConceptsRadiation-induced DNA repairDNA repairCaspase inhibitorsDNA double-strand break repairChemical caspase inhibitorsSpontaneous DNA breakageDNA fragmentationDouble-strand break repairInterference of apoptosisSpecific caspase inhibitorsPulsed-field gel electrophoresisSpontaneous DNA fragmentationGel electrophoresisCell fateBreak repairDNA fragmentsApoptosis inhibitorH2AX activationAgarose plugsDNA breakageApoptosis inhibitionFunctional assaysCaspase-3ApoptosisCell cultures
2010
Cetuximab May Inhibit Tumor Growth and Angiogenesis Induced by Ionizing Radiation: A Preclinical Rationale for Maintenance Treatment After Radiotherapy
Pueyo G, Mesia R, Figueras A, Lozano A, Baro M, Vazquez S, Capella G, Balart J. Cetuximab May Inhibit Tumor Growth and Angiogenesis Induced by Ionizing Radiation: A Preclinical Rationale for Maintenance Treatment After Radiotherapy. The Oncologist 2010, 15: 976-986. PMID: 20798193, PMCID: PMC3228040, DOI: 10.1634/theoncologist.2008-0290.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorKi-67 indexMicrovessel densityAggressive phenotypeTumor growthHigh Ki-67 indexCetuximab maintenance therapyMicroscopic residual diseaseBenefits of radiotherapyVascular endothelial growth factor (VEGF) secretionUntreated cellsGrowth factor secretionMechanism of actionCetuximab maintenanceGrowth factor receptorMaintenance therapyAdjuvant therapyPreclinical rationaleMaintenance treatmentResidual diseaseCarcinoma cell linesClinical evaluationExtracellular signal-related kinaseIrradiated cellsCetuximab