2024
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight J, López-Giráldez F, Choi H, Socci N, Merghoub T, Awad M, Getz G, Gainor J, Hellmann M, Caron É, Kaech S, Politi K. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. Journal Of Experimental Medicine 2024, 222: e20231106. PMID: 39585348, DOI: 10.1084/jem.20231106.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsNon-small cell lung cancerAcquired resistanceCheckpoint inhibitorsResistant tumorsPatients treated with anti-PD-1/PD-L1 therapyAnti-PD-1/PD-L1 therapyLung cancerResistance to immune checkpoint inhibitorsAssociated with decreased progression-free survivalHypoxia activated pro-drugsTargeting hypoxic tumor regionsTreat non-small cell lung cancerAnti-CTLA-4Anti-PD-1Immune checkpoint inhibitionTumor metabolic featuresProgression-free survivalCell lung cancerResistant cancer cellsHypoxic tumor regionsMHC-II levelsRegions of hypoxiaKnock-outCheckpoint inhibitionG9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1
Exposito F, Redrado M, Serrano D, Calabuig-Fariñas S, Bao-Caamano A, Gallach S, Jantus-Lewintre E, Diaz-Lagares A, Rodriguez-Casanova A, Sandoval J, San Jose-Eneriz E, Garcia J, Redin E, Senent Y, Leon S, Pio R, Lopez R, Oyarzabal J, Pineda-Lucena A, Agirre X, Montuenga L, Prosper F, Calvo A. G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1. Cell Death & Disease 2024, 15: 787. PMID: 39488528, PMCID: PMC11531574, DOI: 10.1038/s41419-024-07156-w.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerNon-small cell lung cancer patientsCM-272Treatment of non-small cell lung cancerReprogram tumor cellsAssociated with poor prognosisResponse to chemotherapyCell lung cancerCancer drugsMonitor tumor progressionOverexpression of G9aNSCLC cell linesLung cancer growthCancer drug sensitivityNon-small cell lung cancer growthNon-invasive biomarkersTumor volumeAntitumor efficacyTargeted therapyPoor prognosisCancer modelsTumor cellsInduce cell deathTumor progressionLung cancer
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 inhibitorsPTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.
Exposito F, Redrado M, Houry M, Hastings K, Molero-Abraham M, Lozano T, Solorzano J, Sanz-Ortega J, Adradas V, Amat R, Redin E, Leon S, Legarra N, Garcia J, Serrano D, Valencia K, Robles-Oteiza C, Foggetti G, Otegui N, Felip E, Lasarte J, Paz-Ares L, Zugazagoitia J, Politi K, Montuenga L, Calvo A. PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells. Cancer Research 2023, 83: 2513-2526. PMID: 37311042, DOI: 10.1158/0008-5472.can-22-3023.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerLung squamous carcinomaAnti-PD-1 therapyRegulatory T cellsCell lung cancerImmunosuppressive microenvironmentLung cancerImmunotherapy resistanceT cellsWorse progression-free survivalCell death protein 1PTEN lossAnti-TGFβ antibodyConversion of CD4PI3K/AKT/mTOR pathwayProgression-free survivalDeath protein 1Treatment of miceImmunosuppressive tumor microenvironmentPTEN/PI3K/AKT/mTOR pathwayAKT/mTOR pathwayPD-L1TLR agonistsTumor rejectionSquamous carcinoma
2022
YES1 Is a Druggable Oncogenic Target in SCLC
Redin E, Garrido-Martin EM, Valencia K, Redrado M, Solorzano JL, Carias R, Echepare M, Exposito F, Serrano D, Ferrer I, Nunez-Buiza A, Garmendia I, García-Pedrero JM, Gurpide A, Paz-Ares L, Politi K, Montuenga LM, Calvo A. YES1 Is a Druggable Oncogenic Target in SCLC. Journal Of Thoracic Oncology 2022, 17: 1387-1403. PMID: 35988891, DOI: 10.1016/j.jtho.2022.08.002.Peer-Reviewed Original ResearchConceptsSubpopulation of patientsOncogenic targetsPatient-derived xenograftsMarked antitumor activityGain/amplificationPlasma-derived exosomesDistant metastasisIndependent predictorsTargetable oncogenesPoor prognosisAggressive subtypeClinical managementLung cancerPharmacologic blockadeTumor regressionMouse modelTumor growthPlasma exosomesMolecular subgroupsPharmacologic inhibitionMetastasisAntitumor activityFunctional experimentsOrganoid modelsClinical samplesTwo alternative cell line models for the study of multiorganic metastasis and immunotherapy in Lung Squamous Cell Carcinoma
Valencia K, Sainz C, Bértolo C, de Biurrun G, Agorreta J, Azpilikueta A, Larrayoz MJ, Bosco G, Zandueta C, Redrado M, Redín E, Exposito F, Serrano D, Echepare M, Ajona D, Melero I, Pio R, Thomas R, Calvo A, Montuenga LM. Two alternative cell line models for the study of multiorganic metastasis and immunotherapy in Lung Squamous Cell Carcinoma. Disease Models & Mechanisms 2022, 15: dmm049137. PMID: 34870316, PMCID: PMC8822220, DOI: 10.1242/dmm.049137.Peer-Reviewed Original ResearchConceptsLung squamous cell carcinomaSquamous cell carcinomaLUSC cell linesCell carcinomaCell linesHuman squamous cell carcinomaImmune checkpoint inhibitionAdequate mouse modelsCell line modelsCheckpoint inhibitionImmune landscapeAdrenal glandJ miceMouse modelHuman subtypesMetastatic potentialTumor cell linesCarcinomaRNA sequencingRemarkable heterogeneityHuman diseasesTranscriptomic patternsImmunotherapyMetastasisChloroethylurea
2021
Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
Anfray C, Mainini F, Digifico E, Maeda A, Sironi M, Erreni M, Anselmo A, Ummarino A, Gandoy S, Expósito F, Redrado M, Serrano D, Calvo A, Martens M, Bravo S, Mantovani A, Allavena P, Andón FT. Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity. Journal For ImmunoTherapy Of Cancer 2021, 9: e002408. PMID: 34531246, PMCID: PMC8449972, DOI: 10.1136/jitc-2021-002408.Peer-Reviewed Original ResearchConceptsT cellsSingle treatmentAntitumoral efficacyImmune responseProteomics experimentsProtein-protein interaction analysisFlow cytometryM-CSF-differentiated macrophagesInteraction network analysisAntitumor immune responseRecruitment of CD4Tumor-infiltrating leukocytesAntitumoral immune responseImmunocompetent murine modelInfiltration of macrophagesQuantitative proteomics experimentsLung cancer modelMacrophage cytotoxic activityT cell proliferationTumor-associated macrophagesTLR agonist treatmentCytotoxic activityAntitumor effectorsAntitumoral immunityTumor rechallengeSRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation
Redin E, Garmendia I, Lozano T, Serrano D, Senent Y, Redrado M, Villalba M, De Andrea CE, Exposito F, Ajona D, Ortiz-Espinosa S, Remirez A, Bertolo C, Sainz C, Garcia-Pedrero J, Pio R, Lasarte J, Agorreta J, Montuenga LM, Calvo A. SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation. Journal For ImmunoTherapy Of Cancer 2021, 9: e001496. PMID: 33658304, PMCID: PMC7931761, DOI: 10.1136/jitc-2020-001496.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationDasatinibDrug Resistance, NeoplasmFemaleHumansImmune Checkpoint InhibitorsLung NeoplasmsLymphocytes, Tumor-InfiltratingMiceMice, 129 StrainPhenotypeProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsProto-Oncogene Proteins c-yesSignal TransductionT-Lymphocytes, RegulatoryTumor MicroenvironmentConceptsNon-small cell lung cancerNumber of TregsMultiplex immunofluorescenceAntiprogrammed cell death 1 (PD-1) antibodySrc family kinase (SFK) inhibitor dasatinibTumor growthInhibitor dasatinibCell death 1 antibodyYES1 expressionDeath-1 antibodyImmune cytotoxic activityPD-1 treatmentPD-1/Treg cell conversionUse of dasatinibVivo depletion experimentsAntitumor activityImmune checkpoint inhibitorsOutcomes of patientsProtein expressionCohort of patientsManagement of patientsCell lung cancerRelevant mouse modelVivo drug testing
2020
In vivo efficacy of bevacizumab-loaded albumin nanoparticles in the treatment of colorectal cancer
Luis de Redín I, Expósito F, Agüeros M, Collantes M, Peñuelas I, Allemandi D, Llabot JM, Calvo A, Irache JM. In vivo efficacy of bevacizumab-loaded albumin nanoparticles in the treatment of colorectal cancer. Drug Delivery And Translational Research 2020, 10: 635-645. PMID: 32040774, DOI: 10.1007/s13346-020-00722-7.Peer-Reviewed Original ResearchConceptsAlbumin nanoparticlesHuman serum albumin nanoparticlesAlbumin-based nanoparticlesSerum albumin nanoparticlesPoor tumor penetrationNanoparticlesColorectal cancerTumor penetrationFree bevacizumabXenograft modelAdequate carrierMean sizeHT-29 xenograft modelMetabolic tumor volumePotential undesirable side effectsHuman colorectal cancerTumor growth rateConventional formulationUndesirable side effectsLower incidenceTumor volumeBevacizumabEffective treatmentSide effectsVivo efficacyShort-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade
Ajona D, Ortiz-Espinosa S, Lozano T, Exposito F, Calvo A, Valencia K, Redrado M, Remírez A, Lecanda F, Alignani D, Lasarte J, Macaya I, Senent Y, Bértolo C, Sainz C, Gil-Bazo I, Eguren-Santamaría I, Lopez-Picazo J, Gonzalez A, Perez-Gracia J, de Andrea C, Vicent S, Sanmamed M, Montuenga L, Pio R. Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nature Cancer 2020, 1: 75-85. PMID: 35121837, DOI: 10.1038/s43018-019-0007-9.Peer-Reviewed Original ResearchConceptsPD-1 blockadeCell death protein 1 (PD-1) pathwayPD-1 immune checkpoint blockadeCD8/Treg ratioHigh IGF-1R expressionInsulin-like growth factor-1Cell lung cancer treatmentIGF-1 levelsPD-1 inhibitionImmune checkpoint blockadeTumor-specific immunityCell lung cancerIGF-1R expressionHigher plasma levelsLung cancer progressionLung cancer treatmentIGF-1 receptorGrowth factor-1Protein 1 pathwayTreg ratioCD8 cellsCheckpoint blockadePD-1Syngeneic modelLung cancer
2019
Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1
Villalba M, Redin E, Exposito F, Pajares MJ, Sainz C, Hervas D, Guruceaga E, Diaz-Lagares A, Cirauqui C, Redrado M, Valencia K, de Andrea C, Jantus-Lewintre E, Camps C, Lopez-Lopez R, Lahoz A, Montuenga L, Pio R, Sandoval J, Calvo A. Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1. Scientific Reports 2019, 9: 15400. PMID: 31659178, PMCID: PMC6817908, DOI: 10.1038/s41598-019-51066-3.Peer-Reviewed Original ResearchTargeting of TMPRSS4 sensitizes lung cancer cells to chemotherapy by impairing the proliferation machinery
Exposito F, Villalba M, Redrado M, de Aberasturi AL, Cirauqui C, Redin E, Guruceaga E, de Andrea C, Vicent S, Ajona D, Montuenga LM, Pio R, Calvo A. Targeting of TMPRSS4 sensitizes lung cancer cells to chemotherapy by impairing the proliferation machinery. Cancer Letters 2019, 453: 21-33. PMID: 30905815, DOI: 10.1016/j.canlet.2019.03.013.Peer-Reviewed Original ResearchConceptsTumor growthOverexpression of TMPRSS4Novel therapeutic targetSubcutaneous tumor growthHigh mortality rateLung cancer cellsG2/M phasePoor prognosisTumor engraftmentChemotherapy agentsTherapeutic targetMortality rateNSCLCNovel targetTMPRSS4Cancer cellsDownregulation of genesVivo assaysBiological effectsM phaseKD cellsMolecular mechanismsDownregulationCellsCell cycle
2017
miR-146a targets c-met and abolishes colorectal cancer liver metastasis
Bleau AM, Redrado M, Nistal-Villan E, Villalba M, Exposito F, Redin E, de Aberasturi AL, Larzabal L, Freire J, Gomez-Roman J, Calvo A. miR-146a targets c-met and abolishes colorectal cancer liver metastasis. Cancer Letters 2017, 414: 257-267. PMID: 29133238, DOI: 10.1016/j.canlet.2017.11.008.Peer-Reviewed Original ResearchConceptsCRC liver metastasesLiver metastasesMiR-146aColorectal cancerPrimary tumorColorectal cancer liver metastasesLiver metastatic variantsMC38 adenocarcinoma cellsCancer liver metastasesCRC patientsMajor complicationsTreatment optionsDisease progressionMouse modelMetastasisMetastatic clonesSerial transplantationAdenocarcinoma cellsGene expression arraysHigh expressionMetastatic variantsDeadliest typesNew targetsMicroRNA profilingExpression levels