Featured Publications
Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF–PI3K pathway
Boyer S, Lee H, Steele N, Zhang L, Sajjakulnukit P, Andren A, Ward M, Singh R, Basrur V, Zhang Y, Nesvizhskii A, di Magliano M, Halbrook C, Lyssiotis C. Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF–PI3K pathway. ELife 2022, 11: e73796. PMID: 35156921, PMCID: PMC8843093, DOI: 10.7554/elife.73796.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell Transformation, NeoplasticGene Expression ProfilingGranulocyte-Macrophage Colony-Stimulating FactorHumansMetabolic Networks and PathwaysMetabolomicsMiceMice, Inbred C57BLPancreatic NeoplasmsProteomicsSignal TransductionTranscription FactorsTumor-Associated MacrophagesConceptsTumor-educated macrophagesSingle-cell RNA sequencing datasetsCancer cellsMultiomics characterizationRNA sequencing datasetsTumor-associated macrophagesPI3K-Akt pathwayPI3K pathwayMetabolic programsSequencing datasetsGene expressionMetabolic crosstalkFunction of TAMsCell typesK pathwayGM-CSFGranulocyte-macrophage colony-stimulating factorTumor promotingModel systemEpithelial cellsPathwayColony-stimulating factorMetabolic signaturesMutant KrasMalignant epithelial cellsCysteine depletion induces pancreatic tumor ferroptosis in mice
Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, Sagalovskiy IR, Ma A, Kapilian J, Firl CEM, Decker AR, Sastra SA, Palermo CF, Andrade LR, Sajjakulnukit P, Zhang L, Tolstyka ZP, Hirschhorn T, Lamb C, Liu T, Gu W, Seeley ES, Stone E, Georgiou G, Manor U, Iuga A, Wahl GM, Stockwell BR, Lyssiotis CA, Olive KP. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020, 368: 85-89. PMID: 32241947, PMCID: PMC7681911, DOI: 10.1126/science.aaw9872.Peer-Reviewed Original ResearchConceptsReactive oxygen speciesLipid reactive oxygen speciesPancreatic ductal adenocarcinomaLipid ROS productionAmino acid cysteineCell deathPDAC growthCysteine depletionCoenzyme APDAC cellsTumor ferroptosisROS productionFerroptosisCysteineOxygen speciesCatastrophic accumulationTranslatable meansCancer mortalityDuctal adenocarcinomaLeading causeSystem xTumor typesSubunitsSpeciesDeletionA large-scale analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics
Lee HJ, Kremer DM, Sajjakulnukit P, Zhang L, Lyssiotis CA. A large-scale analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics. Metabolomics 2019, 15: 103. PMID: 31289941, PMCID: PMC6616221, DOI: 10.1007/s11306-019-1564-8.Peer-Reviewed Original ResearchAuditory metabolomics, an approach to identify acute molecular effects of noise trauma
Ji L, Lee HJ, Wan G, Wang GP, Zhang L, Sajjakulnukit P, Schacht J, Lyssiotis CA, Corfas G. Auditory metabolomics, an approach to identify acute molecular effects of noise trauma. Scientific Reports 2019, 9: 9273. PMID: 31239523, PMCID: PMC6592947, DOI: 10.1038/s41598-019-45385-8.Peer-Reviewed Original ResearchConceptsNoise exposureInner earHearing lossNoise-induced hearing lossHidden hearing lossAnimal-based studiesTemporary threshold shiftLow exposure levelsMouse inner earDuration of exposureAuditory traumaLiquid chromatography-coupled tandem mass spectrometryCochlear damageNoise traumaNovel therapiesCochlear functionMetabolic effectsMajor metabolic pathwaysThreshold shiftOxidative stressExposure levelsLC-MS/Molecular effectsEarExposureProteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation
Lee HJ, Jedrychowski MP, Vinayagam A, Wu N, Shyh-Chang N, Hu Y, Min-Wen C, Moore JK, Asara JM, Lyssiotis CA, Perrimon N, Gygi SP, Cantley LC, Kirschner MW. Proteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation. Cell Reports 2017, 20: 721-736. PMID: 28723573, PMCID: PMC5626450, DOI: 10.1016/j.celrep.2017.06.074.Peer-Reviewed Original ResearchConceptsCell cycleCancer-related metabolic pathwaysAmino acid synthesisUpregulation of glycolysisNormal proliferative cellsCellular transitionsMetabolic machineryOxidative phosphorylationLymphocyte cell linesEssential amino acidsMetabolic pathwaysAmino acidsNucleotide synthesisCancer cellsCell linesProteomicsMetabolomic characterizationIL-3Proliferative cellsLipid metabolismUrea cycleCellsMetabolic changesMetabolomic profilingPotential linklinc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells
Tornini V, Miao L, Lee H, Gerson T, Dube S, Schmidt V, Kroll F, Tang Y, Du K, Kuchroo M, Vejnar C, Bazzini A, Krishnaswamy S, Rihel J, Giraldez A. linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells. ELife 2023, 12: e82249. PMID: 37191016, PMCID: PMC10188112, DOI: 10.7554/elife.82249.Peer-Reviewed Original ResearchConceptsCell typesIntergenic non-coding RNAsChromatin architectural proteinCryptic open reading frameGene regulatory networksOpen reading frameNon-coding RNAsNew cell typesNeural cell typesBrain cell typesPutative lincRNAsVertebrate genomesArchitectural proteinsChromatin disruptionChromatin accessibilityRegulatory networksGenetic basisCell developmentMicropeptidesBrain cell developmentReceptor-mediated pathwaySystematic identificationLincRNAsNeural cellsCerebellar cells
2023
Iron promotes glycolysis to drive colon tumorigenesis
Liu Z, Villareal L, Goodla L, Kim H, Falcon D, Haneef M, Martin D, Zhang L, Lee H, Kremer D, Lyssiotis C, Shah Y, Lin H, Lin H, Xue X. Iron promotes glycolysis to drive colon tumorigenesis. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2023, 1869: 166846. PMID: 37579983, PMCID: PMC10530594, DOI: 10.1016/j.bbadis.2023.166846.Peer-Reviewed Original ResearchConceptsGlucose transporter 1Colorectal cancerColon tumorigenesisIron treatmentProgression of CRCCancer-related deathColon tumor growthCommon cancerGlucose levelsColon carcinogenesisGlucose metabolismTumor growthPharmacological inhibitionIntracellular glucose levelsTumor cellsTransporter 1Iron levelsTumor formationAerobic glycolysisPyruvate dehydrogenase kinase 3Excess ironCancerTreatmentGlycolytic productsTricarboxylic acid cycle intermediates
2022
Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome
Zehentmeier S, Lim VY, Ma Y, Fossati J, Ito T, Jiang Y, Tumanov AV, Lee HJ, Dillinger L, Kim J, Csomos K, Walter JE, Choi J, Pereira JP. Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome. Science Immunology 2022, 7: eabo3170. PMID: 36149943, PMCID: PMC9614684, DOI: 10.1126/sciimmunol.abo3170.Peer-Reviewed Original ResearchConceptsSecondary lymphoid organsWHIM syndromeMesenchymal stem cellsInterleukin-7B lymphopeniaBone marrowBM mesenchymal stem cellsT cell numbersIL-7 productionT-cell lymphopeniaLymphotoxin beta receptorEarly progenitor stageLymphoid organsCell lymphopeniaMouse modelBeta receptorsB cellsB cell developmentLymphopeniaStromal cellsLeukocyte retentionSyndromeGOF mutationsLymphopoietic activityCritical pathways
2021
A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation
Kumar R, Landry A, Guha A, Vitvitsky V, Lee H, Seike K, Reddy P, Lyssiotis C, Banerjee R. A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation. Journal Of Biological Chemistry 2021, 298: 101435. PMID: 34808207, PMCID: PMC8683732, DOI: 10.1016/j.jbc.2021.101435.Peer-Reviewed Original Research1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development
Wang T, Wang Z, de Fabritus L, Tao J, Saied EM, Lee HJ, Ramazanov BR, Jackson B, Burkhardt D, Parker M, Gleinich AS, Wang Z, Seo DE, Zhou T, Xu S, Alecu I, Azadi P, Arenz C, Hornemann T, Krishnaswamy S, van de Pavert SA, Kaech SM, Ivanova NB, Santori FR. 1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development. Developmental Cell 2021, 56: 3128-3145.e15. PMID: 34762852, PMCID: PMC8628544, DOI: 10.1016/j.devcel.2021.10.018.Peer-Reviewed Original ResearchConceptsLigand-binding domainNuclear hormone receptor activityTranscriptional networksCellular physiologyCOUP-TFDifferentiation programCell-based assaysHormone receptor activityTranscriptional activityMetabolic enzymesCell developmentPhysiological regulatorPhysiological modulatorBindsPhysiological concentrationsReceptor activityLymphatic vesselsTranscriptionNervous systemNR2F1RegulatorPhenocopiesModulatorEnzymePhysiologyMitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology
Fujiwara H, Seike K, Brooks MD, Mathew AV, Kovalenko I, Pal A, Lee HJ, Peltier D, Kim S, Liu C, Oravecz-Wilson K, Li L, Sun Y, Byun J, Maeda Y, Wicha MS, Saunders TL, Rehemtulla A, Lyssiotis CA, Pennathur S, Reddy P. Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology. Nature Immunology 2021, 22: 1440-1451. PMID: 34686860, PMCID: PMC9351914, DOI: 10.1038/s41590-021-01048-3.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCase-Control StudiesCell CommunicationCells, CulturedColitisColonCytotoxicity, ImmunologicDisease Models, AnimalElectron Transport Complex IIEpithelial CellsFemaleGraft vs Host DiseaseHumansImmunity, MucosalIntestinal MucosaMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicMitochondriaOxidative PhosphorylationSuccinic AcidT-LymphocytesConceptsGenetic experimental approachesCell-intrinsic featuresMetabolic flux studiesIntestinal epithelial cellsOxidative phosphorylationDisease severityT cell-mediated immunopathologyT cell-mediated colitisIntestinal epithelial cell damageProtein analysisSuccinate dehydrogenaseCell-mediated immunopathologyInflammatory bowel diseaseEpithelial cell damageHuman clinical samplesSuccinate levelsEpithelial cellsCritical roleSDHAHost diseaseBowel diseaseComplementary chemicalIntestinal diseaseT cellsMetabolic alterations
2020
Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis
Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, di Magliano M. Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis. Cancer Discovery 2020, 10: 422-439. PMID: 31911451, PMCID: PMC7224338, DOI: 10.1158/2159-8290.cd-19-0958.Peer-Reviewed Original ResearchConceptsPancreatic cancerTreg depletionPancreatic carcinogenesisRegulatory T cellsT cell responsesMyeloid cell recruitmentMouse pancreatic cancerNew therapeutic approachesSmooth muscle actinPromotion of carcinogenesisImmune suppressionImmunosuppressive microenvironmentReceptors CCR1T cellsTherapeutic approachesCell recruitmentMouse modelMyeloid cellsMuscle actinRelated commentaryTumor progressionTregsTumor microenvironmentCancerFibroblast subsets
2019
NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, Caponio D, Khezri R, Demarest TG, Aman Y, Figueroa D, Morevati M, Lee HJ, Kato H, Kassahun H, Lee JH, Filippelli D, Okur MN, Mangerich A, Croteau DL, Maezawa Y, Lyssiotis CA, Tao J, Yokote K, Rusten TE, Mattson MP, Jasper H, Nilsen H, Bohr VA. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nature Communications 2019, 10: 5284. PMID: 31754102, PMCID: PMC6872719, DOI: 10.1038/s41467-019-13172-8.Peer-Reviewed Original ResearchMeSH KeywordsAging, PrematureAnimalsAutophagy-Related Protein-1 HomologCaenorhabditis elegansCation Transport ProteinsDisease Models, AnimalDrosophila melanogasterHumansIntracellular Signaling Peptides and ProteinsMitophagyMutationNADNicotinamide-Nucleotide AdenylyltransferaseWerner SyndromeWerner Syndrome HelicaseConceptsWerner syndromeWerner DNA helicasePremature aging diseaseDrosophila melanogaster modelStem cell dysfunctionCaenorhabditis elegansDNA helicaseOrganismal levelImpaired mitochondrial functionMitochondrial qualityWS phenotypeImpaired mitophagyMitophagyMitochondrial functionDCT-1Ubiquitous moleculeSevere metabolic phenotypeMetabolic phenotypePhenotypeW patientsMetabolic dysfunctionCell dysfunctionMetabolic deficitsTherapeutic interventionsUnderlying mechanismMacrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
Halbrook CJ, Pontious C, Kovalenko I, Lapienyte L, Dreyer S, Lee HJ, Thurston G, Zhang Y, Lazarus J, Sajjakulnukit P, Hong HS, Kremer DM, Nelson BS, Kemp S, Zhang L, Chang D, Biankin A, Shi J, Frankel TL, Crawford HC, Morton JP, Pasca di Magliano M, Lyssiotis CA. Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer. Cell Metabolism 2019, 29: 1390-1399.e6. PMID: 30827862, PMCID: PMC6602533, DOI: 10.1016/j.cmet.2019.02.001.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaTumor-associated macrophagesPancreatic cancer therapyRole of macrophagesAbundant infiltrationGemcitabine therapyGemcitabine treatmentFrontline chemotherapyImmune cellsPancreatic cancerDuctal adenocarcinomaMacrophage burdenMurine modelPharmacological depletionFuture treatmentPDA cellsGemcitabineMacrophagesDrug uptakeMacrophage cellsUnknown physiological roleCancer therapyTherapyPhysiological roleTreatment