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 typesSubunitsSpeciesDeletion