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 ResearchAbnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
Xu J, Reznik E, Lee HJ, Gundem G, Jonsson P, Sarungbam J, Bialik A, Sanchez-Vega F, Creighton CJ, Hoekstra J, Zhang L, Sajjakulnukit P, Kremer D, Tolstyka Z, Casuscelli J, Stirdivant S, Tang J, Schultz N, Jeng P, Dong Y, Su W, Cheng EH, Russo P, Coleman JA, Papaemmanuil E, Chen YB, Reuter VE, Sander C, Kennedy SR, Hsieh JJ, Lyssiotis CA, Tickoo SK, Hakimi AA. Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. ELife 2019, 8: e38986. PMID: 30924768, PMCID: PMC6459676, DOI: 10.7554/elife.38986.Peer-Reviewed Original ResearchConceptsClear cell papillary renal cell carcinomaMtDNA-encoded proteinsPapillary renal cell carcinomaMetabolic phenotypeRenal cell carcinomaNuclear genomeDistinct metabolic phenotypesMitochondrial DNACell carcinomaRespiratory metabolismGenomic sequencingMolecular phenotypesAbnormal oxidative metabolismSugar alcohol sorbitolPresence of glycogenStudy of cancerMajority of cancersOncogenic alterationsPhenotypeOxidative stressOxidative metabolismCytoplasmic clarityDriver lesionsImmunohistochemical stainingKidney tumorsProteomic 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 linkControllability analysis of the directed human protein interaction network identifies disease genes and drug targets
Vinayagam A, Gibson TE, Lee HJ, Yilmazel B, Roesel C, Hu Y, Kwon Y, Sharma A, Liu YY, Perrimon N, Barabási AL. Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 4976-4981. PMID: 27091990, PMCID: PMC4983807, DOI: 10.1073/pnas.1603992113.Peer-Reviewed Original ResearchConceptsPPI networkDisease genesProtein-protein interaction networkDrug targetsCellular information processingHuman PPI networkNovel disease genesCopy number alteration dataPotential drug targetsNumber alteration dataDisease-causing mutationsIndispensable proteinsInteraction networksCell deathGenesProteinCell proliferationDifferent cancersHuman virusesPrimary targetAlteration dataDisease statesTargetMutationsNetwork control propertieslinc-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
2021
1-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
Differential contributions of sarcomere and mitochondria-related multigene variants to the endophenotype of hypertrophic cardiomyopathy
Chung H, Kim Y, Cho SM, Lee HJ, Park CH, Kim JY, Lee SH, Min PK, Yoon YW, Lee BK, Kim WS, Hong BK, Kim TH, Rim SJ, Kwon HM, Choi EY, Lee KA. Differential contributions of sarcomere and mitochondria-related multigene variants to the endophenotype of hypertrophic cardiomyopathy. Mitochondrion 2020, 53: 48-56. PMID: 32380161, DOI: 10.1016/j.mito.2020.04.010.Peer-Reviewed Original ResearchConceptsNon-apical hypertrophic cardiomyopathyApical hypertrophic cardiomyopathyHypertrophic cardiomyopathyHCM patientsIndividualized risk stratificationComprehensive genetic testAtrium remodelingDiastolic dysfunctionRisk stratificationPoor prognosisSarcomere mutationsPatientsPathogenic variantsRare variant analysisAsian populationsPathogenic mutationsRegulatory 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 mechanismHydrogen sulfide perturbs mitochondrial bioenergetics and triggers metabolic reprogramming in colon cells
Libiad M, Vitvitsky V, Bostelaar T, Bak DW, Lee HJ, Sakamoto N, Fearon E, Lyssiotis CA, Weerapana E, Banerjee R. Hydrogen sulfide perturbs mitochondrial bioenergetics and triggers metabolic reprogramming in colon cells. Journal Of Biological Chemistry 2019, 294: 12077-12090. PMID: 31213529, PMCID: PMC6690701, DOI: 10.1074/jbc.ra119.009442.Peer-Reviewed Original ResearchConceptsSulfide quinone oxidoreductaseSulfide oxidation pathwayElectron transfer chainColon epithelial cellsMetabolic reprogrammingGlutamine-dependent reductive carboxylationMitochondrial bioenergeticsMitochondrial sulfide oxidation pathwayCentral carbon metabolismEpithelial cellsHost-microbiome interfaceS oxidation pathwayCarbon metabolismHuman colonic cryptsOxidation pathwayPathway enzymesCellular bioenergeticsGut microbial metabolismStress responseMicrobial metabolismTransfer chainReductive carboxylationReductive shiftOxygen consumption rateQuinone oxidoreductaseMacrophage-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