2024
Overexpression 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 1MicroenvironmentPlasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma
Kim I, Diamond M, Yuan S, Kemp S, Kahn B, Li Q, Lin J, Li J, Norgard R, Thomas S, Merolle M, Katsuda T, Tobias J, Baslan T, Politi K, Vonderheide R, Stanger B. Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma. Nature Communications 2024, 15: 1532. PMID: 38378697, PMCID: PMC10879147, DOI: 10.1038/s41467-024-46048-7.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaEpithelial-to-mesenchymal transitionResistance to immunotherapyT cell killingDuctal adenocarcinomaAcquired resistance to immunotherapyResistance to cancer immunotherapyMouse model of pancreatic ductal adenocarcinomaModel of pancreatic ductal adenocarcinomaExpression of immune checkpointsInterferon regulatory factor 6Effect of TNF-aEMT transcription factor ZEB1Antigen presentation machineryTumor immune microenvironmentCell-intrinsic defectsPro-apoptotic effectsPresentation machineryCancer immunotherapyImmune checkpointsTumor relapseImmune microenvironmentPrimary resistanceT cellsAcquired resistance
2023
Autologous 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 ResearchMeSH KeywordsAnimalsDisease Models, AnimalHumansMedical OncologyMiceNeoplasmsTumor MicroenvironmentVascular Endothelial Growth Factor AConceptsHuman 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 carcinoma
2022
Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
Adua S, Arnal-Estapé A, Zhao M, Qi B, Liu Z, Kravitz C, Hulme H, Strittmatter N, López-Giráldez F, Chande S, Albert A, Melnick M, Hu B, Politi K, Chiang V, Colclough N, Goodwin R, Cross D, Smith P, Nguyen D. Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer. Nature Communications 2022, 13: 7690. PMID: 36509758, PMCID: PMC9744876, DOI: 10.1038/s41467-022-34889-z.Peer-Reviewed Original ResearchConceptsGene expression programsRas homolog family member ACancer cellsFamily member AEpidermal growth factor receptorExpression programsMetastatic cancer cellsSRF signalingGrowth factor receptorTumor microenvironmentLung cancerFunctional linkExtracellular lamininDrug-resistant cancer cellsMutant non-small cell lung cancerNon-small cell lung cancerCentral nervous system relapseMolecular studiesMember AEGFR-mutant lung cancerFactor receptorNervous system relapseCell lung cancerDisseminated tumor cellsBrain tumor microenvironment