Francisco Exposito, PhD
Postdoctoral AssociateAbout
Research
Publications
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
Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer
Stockhammer P, Grant M, Wurtz A, Foggetti G, Expósito F, Gu J, Zhao H, Choi J, Chung S, Li F, Walther Z, Dietz J, Duffield E, Gettinger S, Politi K, Goldberg S. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer. Journal Of Thoracic Oncology 2023, 19: 240-251. PMID: 37806385, PMCID: PMC11364167, DOI: 10.1016/j.jtho.2023.10.001.Peer-Reviewed Original ResearchProgression-free survivalEGFR-mutant NSCLCTP53 mutationsOverall survivalClinical outcomesEGFR-TKIInferior outcomesWorse outcomesYale cohortMetastatic EGFR-mutant NSCLCShorter progression-free survivalEGFR-mutant lung cancerTyrosine kinase inhibitor therapyFirst-line TKIYale Cancer CenterSecond-line therapyInferior clinical outcomesSubset of patientsKinase inhibitor therapyAdditional therapeutic interventionsAggressive disease phenotypeCo-occurring alterationsTumor suppressor gene alterationsTumor genomic profilingMultiple tumor suppressor genesMammalian 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 carcinomaCancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer
Otegui N, Houry M, Arozarena I, Serrano D, Redin E, Exposito F, Leon S, Valencia K, Montuenga L, Calvo A. Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer. Cancers 2023, 15: 3076. PMID: 37370686, PMCID: PMC10295869, DOI: 10.3390/cancers15123076.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsLung cancer patientsSmall cell lung cancerCancer patientsTumor microenvironmentLung cancerEffects of ICIsEfficacy of ICIsChimeric antigen receptor cellsCell lung cancer patientsCytotoxic T cellsImmunosuppressive tumor microenvironmentCell-extrinsic mechanismsCell-intrinsic alterationsGreat clinical successLack of responseCheckpoint inhibitorsICI responseTherapeutic responseT cellsDNA damage repair pathwaysClinical successImmunotherapyMetabolic alterationsTherapeutic interventions
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 rechallengeCancer Epigenetic Biomarkers in Liquid Biopsy for High Incidence Malignancies
Palanca-Ballester C, Rodriguez-Casanova A, Torres S, Calabuig-Fariñas S, Exposito F, Serrano D, Redin E, Valencia K, Jantus-Lewintre E, Diaz-Lagares A, Montuenga L, Sandoval J, Calvo A. Cancer Epigenetic Biomarkers in Liquid Biopsy for High Incidence Malignancies. Cancers 2021, 13: 3016. PMID: 34208598, PMCID: PMC8233712, DOI: 10.3390/cancers13123016.Peer-Reviewed Original ResearchLiquid biopsyEpigenetic biomarkersSpecific epigenetic alterationsDNA methylation changesTumor microenvironmentDNA promoter methylationCommon clinical practiceHigh-incidence malignancyActionable genetic alterationsCancer drug responseSingle geneEpigenetic eventsDNA methylationGene setsMethylation changesTypes of cancerEpigenetic alterationsPrimary tumorClinical trialsClinical valueCerebrospinal fluidHigh incidenceTissue biopsiesClinical practiceEarly alterations