Rewiring Cancer Metabolism | Harvard Medical School

For the past 10 to 15 years, most researchers working in cancer metabolism have held that cancer cells do Warburg glycolysis to send glucose for ... Skiptomaincontent CampusAlert ReturningtoCampusInformationfortheHMSCommunity(UpdatedMay2,2022) Close MobileMainNavigation MobileUtilityNavigation News&Research RewiringCancerMetabolism Researchfindsnondividingcoloncancercellsusealteredglucosemetabolism ByALICEMcCARTHY|MGHNewsandPublicAffairs March24,2022 Research CareDelivery 4minread Microscopicimageofcolonicadenocarcinoma.Image:MdArifulIslam/iStock/GettyImagesPlus   HarvardMedicalSchoolresearchershaverevealednewinsightsintotheadaptationscancercellsmaketorewiretheirmetabolismtoachievegrowthandsurvive. Thediscoveries,publishedinNatureCommunications,includeachallengetoawell-knownfeatureincancermetabolismandraisethecallfortoolstostudycancercellmetabolismonanearlysingle-celllevel. GetmoreHMSnewshere Inthe1920s,NobellaureateOttoWarburgobservedthatcancercellsmetabolicallyadapttheirglucosepathwayinunusualways. Normally,glucose—themainnutrientneededforcellstofunction—issenttothecell’smitochondriatobebrokendownforenergy,aprocessthatrequiresoxygen. Cancercells,however,appeartorapidlyincreasetheirglucoseuptakeanddirectlyfermentitintolactate,eveninthepresenceofoxygenandfunctionalmitochondria. “Hecalleditaerobicglycolysis,butweknowitastheWarburgeffect,”saidthepaper’sleadauthor RaulMostoslavsky,theHMSLaurelSchwartzProfessorintheFieldofOncologyandscientificco-directoroftheMassachusettsGeneralHospitalCancerCenter. Fornearly15yearsresearchershavebeentryingtoexplain whycancercellsdothis.  Mostoslavsky’steamstudiedcoloncancertumorstolearnmore,developingafluorescentreporterthatstainedonlyamarkerofglycolysisincellsofthetumor. UsingthisreporterandamassspectrometryimagingapproachdevelopedbycollaboratorNathalieAgar,HMSassociateprofessorofneurosurgeryatBrighamandWomen’sHospital,theresearchersfoundthatnotallcellswithinthecoloncancercellreliedonWarburgglycolysis. “Wefoundthatthismetabolicadaptationdoesnothappeninthewholetumor,onlyinaheterogeneousgroupthatwerenotdividing,”saidMostoslavsky. Histeamhadpreviouslypublishedthisheterogeneousfeature insquamouscellcarcinoma butthisisthefirsttimeithasbeenshownincoloncancerandinnondividingcells.  “Whatreallysurprisedusisthatwhenwestainedthetumorcellswithamarkerofcellproliferation,theyweremutuallyexclusive,”addedMostoslavsky. Withinfullytransformedcoloncancers,thecellsthatweredoingWarburgglycosiswerenotdividing. “ThiscompletelychallengesthedogmaoftheWarburgeffect,”Mostoslavskysaid. Forthepast10to15years,mostresearchersworkingincancermetabolismhaveheldthatcancercellsdoWarburgglycolysistosendglucoseforbiomassproduction,orrapidproliferation. “Instead,wefoundthatthemainreasontheyweredoingitwastoreducereactiveoxygenspecies,orROS,”hesaid. Reactiveoxygenspeciesdamagecellsduringglucosebreakdownandenergyproduction.“ThecellsdoWarburgmetabolismtoprotectagainstaccumulationofROS,”Mostoslavskysaid. TheresearchshowedthatindeedWarburgglycolysisisrealandfunctionalincancercellsasaneededadaptation. “Butit’snotforthereasonweusedtothink,”saidMostoslavsky.“Thismeansweneedtorethinkhowwearestudyingcancermetabolism.” Muchoftheadvancementmadeinthepast10yearsstudyingcancermetabolismcomesfrommassspectrometryanalysisofmetabolomics,whichrequiremanycells.Theproblemisalackofmeansforanalyzingcellularheterogeneity. “Ifmetabolicadaptationhappensinsomecancercellsornotinothers,youwillnotbeabletodeterminethatwiththecurrenttechnologiesthatexist,”Mostoslavskysaid.“WenowknowWarburgglycolysisisaheterogeneousfeaturehappeningintumors,soweneedtodeveloptoolsthatwillallowustoinvestigatetumorsinasingle-cellfashion.” Inthepaper,theteamreliedonanovelmassspectrometryimagingtooldevelopedtoachievedataalmostatasinglecellresolution. “Itisclearthatcancermetabolismishighlyheterogeneous,sowewillneednewtoolslikethistostudyanddefinethesemetabolicfeaturesintumors,”saidMostoslavsky. AdditionalauthorsincludeChristinaFerrer,Jee-EunChoi,ManasviShah,SylwiaStopka,AndrewPerciaccante,NiyataDesai,DianeCapen,MuratCetinbas,RuslanSadreyev,DennisBrown,MiguelRivera,andDavidBreault. ThisworkwassupportedbygrantsfromtheNationalInstitutesofHealth,FPRC5permille2011MIUR,FPRC5permille2014MIUR,RC2018MinisterodellaSalute,andHorizon2020:EUProgrammeforResearchandInnovation. AdaptedfromaMassGeneralnewsrelease.  RelatedNews EarlyWarningSystem? May5,2022 Accumulationofamyloid-betaandtauproteinscandisruptbrainconnectivityyearsbeforeAlzheimer... RemakingHealth,Sciences&Technology March22,2022 At50-yearmark,HSTembarksonbroadcurriculumreform Heart-SavingAI March21,2022 Anartificial-intelligencesystemshowspromiseinidentifyingsignsofhearttransplantrejection.... 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