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 inhibitionOverexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment
Martinez-Terroba E, Plasek-Hegde L, Chiotakakos I, Li V, de Miguel F, Robles-Oteiza C, Tyagi A, Politi K, Zamudio J, Dimitrova N. Overexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment. Science Immunology 2024, 9: eadh5462. PMID: 38875320, DOI: 10.1126/sciimmunol.adh5462.Peer-Reviewed Original ResearchConceptsTumor microenvironmentLung adenocarcinomaMetastatic diseasePromoting metastatic diseaseGlobal chromatin accessibilityMetastasis-associated lung adenocarcinoma transcript 1Overexpression of MALAT1Lung adenocarcinoma transcript 1Lung adenocarcinoma metastasisCCL2 blockadeInflammatory reprogrammingEnhanced cell mobilityMacrophage depletionMechanism of actionTumor typesTumor progressionMouse modelCell mobilizationTumorLong noncoding RNAsParacrine secretionMetastasisCell linesTranscript 1Microenvironment
2023
Oncogenic context shapes the fitness landscape of tumor suppression
Blair L, Juan J, Sebastian L, Tran V, Nie W, Wall G, Gerceker M, Lai I, Apilado E, Grenot G, Amar D, Foggetti G, Do Carmo M, Ugur Z, Deng D, Chenchik A, Paz Zafra M, Dow L, Politi K, MacQuitty J, Petrov D, Winslow M, Rosen M, Winters I. Oncogenic context shapes the fitness landscape of tumor suppression. Nature Communications 2023, 14: 6422. PMID: 37828026, PMCID: PMC10570323, DOI: 10.1038/s41467-023-42156-y.Peer-Reviewed Original ResearchAutologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Chiorazzi M, Martinek J, Krasnick B, Zheng Y, Robbins K, Qu R, Kaufmann G, Skidmore Z, Juric M, Henze L, Brösecke F, Adonyi A, Zhao J, Shan L, Sefik E, Mudd J, Bi Y, Goedegebuure S, Griffith M, Griffith O, Oyedeji A, Fertuzinhos S, Garcia-Milian R, Boffa D, Detterbeck F, Dhanasopon A, Blasberg J, Judson B, Gettinger S, Politi K, Kluger Y, Palucka K, Fields R, Flavell R. Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment. Journal For ImmunoTherapy Of Cancer 2023, 11: e006921. PMID: 37487666, PMCID: PMC10373695, DOI: 10.1136/jitc-2023-006921.Peer-Reviewed Original ResearchConceptsHuman tumor microenvironmentTumor microenvironmentTumor-immune interactionsSolid tumorsAdaptive immune activationAdaptive immune populationsIndividual tumor microenvironmentsPatient's hematopoietic systemPatient-derived xenograft tissuesVascular endothelial growth factorBone marrow hematopoietic stemBone marrow aspiratePreclinical drug testingEndothelial growth factorHematopoietic systemAutologous tumorPDX modelingPDX miceImmune activationImmune populationsMarrow aspiratesAutologous systemIndividual patientsLittermate controlsPreclinical predictionsPTEN 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 carcinomaChallenges and opportunities for modeling aging and cancer
Anczuków O, Airhart S, Chuang J, Coussens L, Kuchel G, Korstanje R, Li S, Lucido A, McAllister S, Politi K, Polyak K, Ratliff T, Ren G, Trowbridge J, Ucar D, Palucka K. Challenges and opportunities for modeling aging and cancer. Cancer Cell 2023, 41: 641-645. PMID: 37001528, PMCID: PMC10185379, DOI: 10.1016/j.ccell.2023.03.006.Peer-Reviewed Original ResearchAn intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1
Aftab F, Rodriguez-Fuguet A, Silva L, Kobayashi I, Sun J, Politi K, Levantini E, Zhang W, Kobayashi S, Zhang W. An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1. British Journal Of Cancer 2023, 128: 1647-1664. PMID: 36810913, PMCID: PMC10133251, DOI: 10.1038/s41416-023-02196-z.Peer-Reviewed Original ResearchConceptsProtein-protein interactionsProximity ligation assayWhole transcriptomic profileEGFR inhibitorsMUC1-CTThermal stability assaysRNA sequencingTransgenic micePurine biosynthesisTranscriptomic profilesAICARTumor cell growthLigation assayMucin 1DNA damageCell growthMethodsCell viabilityLung tumor tissuesTumor formationCancer cellsEGFR-mutant lung cancerStability assaysJAKJAK1Dual immunofluorescence staining
2017
Genome-Wide RNA Interference: Functional Genomics in the Postgenomics Era.
Politi K, Wajapeyee N. Genome-Wide RNA Interference: Functional Genomics in the Postgenomics Era. Cold Spring Harbor Protocols 2017, 2017: pdb.top097550. PMID: 28864574, DOI: 10.1101/pdb.top097550.Chapters
2012
Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response
Sangodkar J, Dhawan N, Melville H, Singh V, Yuan E, Rana H, Izadmehr S, Farrington C, Mazhar S, Katz S, Albano T, Arnovitz P, Okrent R, Ohlmeyer M, Galsky M, Burstein D, Zhang D, Politi K, DiFeo A, Narla G. Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response. Journal Of Clinical Investigation 2012, 122: 2637-2651. PMID: 22653055, PMCID: PMC3386822, DOI: 10.1172/jci62058.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAdenocarcinomaAdenocarcinoma of LungAnimalsAntineoplastic AgentsCell Line, TumorDrug Resistance, NeoplasmDrug SynergismEnzyme ActivationErbB ReceptorsErlotinib HydrochlorideFemaleForkhead Box Protein O1Forkhead Transcription FactorsGene Expression Regulation, NeoplasticHumansKruppel-Like Factor 6Kruppel-Like Transcription FactorsLung NeoplasmsMiceMice, Inbred BALB CMice, NudeMutationProto-Oncogene ProteinsProto-Oncogene Proteins c-aktQuinazolinesReal-Time Polymerase Chain ReactionSignal TransductionTranscription, GeneticTrifluoperazineTumor BurdenXenograft Model Antitumor AssaysConceptsAnti-EGFR-based therapyEGFR signalingKruppel-like factor 6Lung adenocarcinomaForkhead box O1Xenograft models of lung adenocarcinomaModel of lung adenocarcinomaMetastatic lung adenocarcinomaTreat advanced cancersMolecular drivers of disease progressionDrivers of disease progressionOncogenic EGFR signalingActivation of Akt signalingFoxO1 nuclear exportTreating resistant diseaseIn vivo modelsCell culturesErlotinib resistanceResistant diseaseTreatment responseMolecular therapiesXenograft modelFDA-approved drugsDisease progressionEGFR activation
2005
Oncogenes Come of Age
VARMUS H, PAO W, POLITI K, PODSYPANINA K, DU Y. Oncogenes Come of Age. Cold Spring Harbor Symposia On Quantitative Biology 2005, 70: 1-9. PMID: 16869733, PMCID: PMC1791364, DOI: 10.1101/sqb.2005.70.039.Chapters