Sugar? No Thank You, Just a Deep Breath of Oxygen for Cancer Stem Cells

2013).WhethertransferofFasmRNA

didnotinvestigateifsecretoryfactors

otherthanEVscouldsupplementFas

function,itisdifficulttoimaginehowcyto-

MSC-EVscandirectlyinteractwithtis-

witheachotherbydisseminatinganti-

gen-specificinformationviaEVs(ELAn-

daloussietal.,2013).Likewise,MSC-

Brint,E.,O’Callaghan,G.,andHouston,A.(2013).

Gnecchi,M.,Zhang,Z.,Ni,A.,andDzau,V.J.

(2008).Circ.Res.103,1204–1219.

Liu,S.,Liu,D.,Chen,C.,Hamamura,K.,Mosha-

Y

2

Center,

ndrial

factorsistypicallynecessarytoelicit

epigeneticchanges(Mohammadand

Baylin,2010).Theabilityofasecretome

toinduceepigeneticchangesacross

Fas

lpr

MSCsatdifferentsitesinthebone

marrowimpliesamoresophisticatedma-

chinery(perhapsEVs)thatco-delivers

multiplesignalsperinteractionwitha

cell.Indeed,EV-mediatedeffectscanbe

sopotentthatinmanystudies,including

Liuetal.(2015),MSC-EVsalonecan

Sugar?NoThank

ofOxygenforCancer

AndreaViale

1,2,

andGiulioF.Draetta

1,

1

DepartmentofGenomicMedicine

2

DepartmentofMolecularandCellularOncology

TheUniversityofTexasMDAndersonCancer

Correspondence:[e-mail]

http://dx.doi.org/10.1016/j.cmet.2015.09.020

Tumorsaremetabolicallyheterogeneous

describedtorelymoreonmitocho

Sanchoetal.(2015)demonstratethat

populationsofpancreatictumorcells

Whenmetazoansevolved,cellslostthe

abilitytoproliferateinresponsetothe

availabilityofnutrientsinthemicroenvi-

ingacomplexsignalingnetworksimilar

toendocrinepathways.Wild-typeMSC-

EVsmaythereforeeffectepigenetic

changesinmanymorecelltypesbesides

Fas

lpr

MSCs,whichcouldexplainthe

reversaloftissuedamageinmultipleor-

gansasobservedbyLiuetal.(2015).

Theabilityofastemcelltherapyorits

secretoryproductstoerasepathological

‘‘memory’’andcoaxdiseasedcellsto

adoptahealthyphenotypeprovides

ou,JustaDeepBreath

StemCells

Houston,TX77030,USA

,andsubpopulationsoftumor

respirationthanglycolysisfor

MYCisamasterswitchregulatingmetabo

.

ronment,abehaviorthatpersistsinall

single-cellbeingsfrombacteriatoeukary-

oticmicroorganism.Thelossofnutrient-

CellMetabolism22

Biotechnol.28,1033–1038.

Ranganath,S.H.,Levy,O.,Inamdar,M.S.,and

Karp,J.M.(2012).CellStemCell10,244–258.

Rani,S.,Ryan,A.E.,Griffin,M.D.,andRitter,T.

(2015).Mol.Ther.23,812–823.

Tomasoni,S.,Longaretti,L.,Rota,C.,Morigi,M.,

Conti,S.,Gotti,E.,Capelli,C.,Introna,M.,Re-

muzzi,G.,andBenigni,A.(2013).StemCells

Dev.22,772–780.

vonBahr,L.,Batsis,I.,Moll,G.,Ha¨gg,M.,Szakos,

A.,Sundberg,B.,Uzunel,M.,Ringden,O.,andLe

Blanc,K.(2012).StemCells30,1575–1578.

igeniccellshavebeenrecently

energyproduction.Inthisissue,

licprogramsindifferentsub-

kinesandsmallmoleculescanupregulate

FasincellsthatlackafunctionalFas

gene.Acomplexinterplayofsignaling

EVsmayinteractwithintermediarycells

thatinturnreleasesignalsthatmay

includeEVstodamagedtissues,launch-

verinia,A.,Yang,R.,Liu,Y.,Jin,Y.,andShi,S.

(2015).CellMetab.22,thisissue,606–618.

Mohammad,H.P.,andBaylin,S.B.(2010).Nat.

couldbeanalternativemechanismto

supplementFasfunctionremainstobe

determined.

Meanwhile,althoughLiuetal.(2015)

sue-specificcellsasLiuetal.(2015)

demonstrate,indirectinteractionsshould

notbeoverlooked.Mountingevidencein-

dicatesthatimmunecellscommunicate

Cell.Mol.LifeSci.70,4085–4099.

ELAndaloussi,S.,Ma¨ger,I.,Breakefield,X.O.,and

Wood,M.J.A.(2013).Nat.Rev.DrugDiscov.12,

347–357.

suggestedbyLiuetal.(2015).Potentially,

wild-typeMSC-EVscouldalsotransfer

mRNA,miRNA,cytosolicproteins,and

othermembraneproteinstoelicitand/or

potentiatetheobservedepigenetic

changes.Previousworkbyothers

showedthatMSC-EVscanupregulate

expressionofagrowthfactorreceptorin

recipientcellsbytransferringmRNAen-

codingthereceptor(Tomasonietal.,

reproducethetherapeuticbenefitsof

MSCs(Ranietal.,2015).LikeMSCs,

MSC-EVshavebeenshowntoalleviate

damageinorgansincludingtheheart,

lungs,kidneys,andliverandinsystemic

diseasessuchasgraft-versus-hostdis-

ease(Ranietal.,2015).BecauseEVs

co-delivermultiplesignals,delineating

themechanismsofactionofMSC-EVsis

notstraightforward.Moreover,while

hopeforregenerativemedicineoreven

rejuvenation.Whethersuchamechanism

canbeharnessedtoachievelong-term

therapeuticeffects,however,isworthy

offurtherinvestigation.

REFERENCES

Ankrum,J.A.,Ong,J.F.,andKarp,J.M.(2014).Nat.

Biotechnol.32,252–260.

CellMetabolism

Previews

regulatedproliferationisanessential

adaptationformulticellularorganisms

tomaintainspatialcontrolofcomplex

,October6,2015a2015ElsevierInc.543

tissues.Theuncouplingofthecellcycle

fromfoodaccessibilityisachievedby

restrictingcells’accesstofood.Instead

offreelyuptakingnutrientsfrominterstitial

fluid,cellsmustfirstreceivesignalsby

specificgrowthfactorsinordertopro-

liferate.Thesecoordinateametabolicpro-

gramthatinducestheexpressionofmem-

branetransportersandanabolicenzymes

responsibleforfueluptakeandconver-

sionintobiomass(WardandThompson,

2012).Itisfascinatingthatincancer,a

conditioninwhichcellsescapethetight

controlofsignalscontrollingproliferation,

cellsalsobecomeindependentfrom

exogenoussignalsthatgovernnutrient

uptake(WardandThompson,2012).

Indeed,tumorcellsreacquiretheability

tofreelyuptakefoodfromthemicroenvi-

ronment,e.g.,glucose,apropertyconsid-

eredcommontomanytumorsandwidely

exploitedfortumordetectionusingPET

imaging.Inthisissue,Sanchoetal.

(2015)challengethisunifyingviewoftu-

mormetabolismisolatingasubpopulation

oftumorcellscharacterizedbydecreased

dependencyonglucoseandincreased

mitochondrialrespiration(OXPHOS).

Figure1.MYCIsaMasterRegulatorofCancer

MYCisatranscriptionalrepressorofPGC1aandregulates

populationsoftumorcells.Incancerstemcells,lowlevels

releasetheexpressionofPGC1athat,inturn,sustains

differentiatedcancercells,theupregulationofMYCis

suppressionofOXPHOS.Becausecancerstemcells

hibitorsspecificallytargetcancerstemcells,thoughthey

partialupregulationofMYCthatorchestratesanintermediate

544CellMetabolism22,October6,2015a2015

Theobservationthattumorshave

alteredmetabolismwithrespectto

normaltissuesisatleastacenturyold,

withthefirstformalmodelproposedby

OttoWarburg.Warburg’shypothesis

thattumorcellsaremoreglycolytic(aero-

bicglycolysis)comparedtonormalcells

andhavedefectivemitochondriadomi-

natedthefieldofcancermetabolism

fordecadesandwasbolsteredbyour

progressioninunderstandingmolecular

mechanismsunderlyingmetabolicre-

programmingincancercells(VanderHei-

denetal.,2009).Ofcourse,wenowhave

remarkabledocumentationoftheinterre-

latednessofgeneticmutationsandmeta-

bolictransformation,whichhasclarified

theroleofbothoncogenesandtumor

suppressorgenesindrivingmetabolic

reprogrammingincancercells(Kim

andDang,2006;WardandThompson,

2012).Notably,activationofKRASand

MYC,aswellasinactivationofTP53,

canextensivelyreprogramcellmeta-

bolism,modulatingseveralbiosynthetic

pathwaysnecessarytosustaintumor

growth.Thefinaloutcomeofsuchmeta-

bolictransformationisthatcellsuptake

Metabolism

themetabolicprogramindifferentsub-

ofMYCexpressionsuppressglycolysisand

mitochondrialrespiration(OXPHOS).Inmore

responsiblefortheirglycolyticmetabolismandthe

relyonOXPHOSfortheirenergetics,OXPHOSin-

caneventuallydevelopresistancethrougha

glycolytic/OXPHOSmetabolism.

ElsevierInc.

morefuelindependentlyofexogenous

signals,producemorelactate,and

consumelessoxygenbecausecarbon

skeletonsinthetricarboxylicacidcycle

aredivertedtofuelanabolicreactions

forbiomasssynthesisinsteadofbeing

completelyoxidizedtoproduceATP

throughrespiration.Indeed,aerobic

glycolysisisanessentialtumoradapta-

tionmechanism;however,agrowing

bodyofevidencesupportstheidea

thattumorsaremuchmoreheteroge-

neousthanpreviouslythought,andthat

aerobicglycolysisrepresentsjustone

aspectofacomplexmetaboliclandscape

amongtumorcells(Vialeetal.,2015).

Asmallpopulationofslow-growingcells

endowedwithtumorigenicpotential,

self-renewalcapabilities,andintrinsic

resistancetoconventionalandtargeted

therapieshasbeenisolatedandchar-

acterizedindifferenttumors.Thesecells

seemtorelyonmoreactivemitochon-

driathanothertumorcellsandshowan

increasedconsumptionofoxygen(Laga-

dinouetal.,2013;Roeschetal.,2013;Vi-

aleetal.,2014).Interestingly,acommon

traitamongthissubpopulationofcells

istheirdecreasedglycolyticcapacity

andtheinabilitytoupregulateglycolysis

inresponsetotheinhibitionofmitochon-

drialrespiration.Thisisacriticalfeature

ofthemetabolismoftumorigeniccells,

revealingalackofenergeticcompensa-

torymechanisms(Vialeetal.,2014).The

strictdependencyonOXPHOSformain-

tainingenergyrequirementshaslead

severalauthorstoproposetheuseofin-

hibitorsofOXPHOStoselectivelyeradi-

catecancerstemcellspreventingtumor

relapseaftertreatment(Roeschetal.,

2013;SkrtiC19cetal.,2011;Vialeetal.,

2014,2015;Wolf,2014).Withthisambi-

tiousgoal,somepromisingcandidates,

suchastigecycline,arealreadyunder

clinicalinvestigation.

InthisissueofCellMetabolism,Sancho

etal.(2015),usingcellsisolatedfromhu-

manprimarytumors,demonstratedthat

pancreaticcancersaremetabolically

heterogeneous,withmetabolicprograms

activatedindifferentsubpopulationsof

cells:cancerstemcellsrelyonOXPHOS

CellMetabolism

Previews

andhavedecreasedglycolyticactivity

withrespecttotheirmoredifferentiated

progeny.Becausecancerstemcells

donotcompensateinhibitionofmito-

chondrialrespirationwithanincreasein

glycolysis,theauthorsdemonstrated

thattargetingOXPHOSisauseful

approachtoeliminatetumorigeniccells

inxenograftmodelsofpatient-derived

tumor.Indeed,treatmentwithMetformin,

acomplexIinhibitorwidelyusedas

hypoglycemicdrugintype2diabetes,

inducesspecificallymetabolicstress

andapoptosisincancerstemcellsand,

consequently,areductionofCD133+

tumorigeniccellsintumorsinvivo.How-

ever,eventuallymetforminresistance

emergesandtumorsregrow.Interest-

ingly,theauthorsfoundthatcancerstem

cellsresistanttoOXPHOSinhibition

activatedaglycolyticprogram,acquiring

an‘‘intermediateglycolytic/respiratory’’

metabolism.Transcriptionalanalysis

comparingcancerstemcellswiththeir

other,thusregulatingthetransitionbe-

tweencancerstemcellsandtheirmore

differentiatedprogenyandexplainingthe

‘‘intermediatemetabolism’’ofOXPHOS

inhibitor-resistantcancerstemcellsas

well(Figure1).

Thesefindingsuncovernewmolecular

mechanismsresponsibleformetabolic

heterogeneityinpancreatictumorsand

identifyanunexpectedfunctionofMYC.

Thisworkraisesimportantquestions

aswell.Forexample,ifactivatedonco-

geneshavetheabilitytoreprogramthe

metabolismoftransformedcells,whyis

theiroutcomedifferentindistinctsub-

populationsofcells?Inotherwords,if

KRASisexpressedinallthetumorsub-

populations,whydoesitexertdifferent

understandingtumorheterogeneityand

complexity.

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etal.(2015).CellMetab.Publishedonline

CellMetabolism

Previews

differentiatedprogenyandresistantcan-

cerstemcellsrevealedthatexpression

ofMYCwasincreasedinOXPHOSinhib-

itor-resistantcancerstemcellsatlevels

comparabletothosefoundinmorediffer-

entiatedtumorcells.Importantly,theau-

thorsdemonstratedthatMYCactedas

the‘‘mainswitch’’betweenglycolytic

andoxidativemetabolismincancercells;

indeed,theydemonstratedthatMYCisa

directtranscriptionalinhibitorofthemito-

chondrialmasterregulatorPeroxisome

proliferator-activatedreceptorgamma

coactivator1-alpha(PGC1a).Asaconse-

quence,expressionofMYCactivates

glycolyticprogramsononehandandsup-

pressesmitochondrialrespirationonthe

metaboliceffectsincancerstemcells,

theirdifferentiatedprogeny,andeventu-

allyinOXPHOSinhibitor-resistantcan-

cerstemcells?WhyisMYCactivatedin

onlysomesubpopulationsandnotin

others?

Thesedataportendamodelinwhich

theeffectsofactivatedoncogeneson

metabolicreprogrammingarenotuniver-

salbutcontext-specificsuchthatthe

extentoftheeffectofKRASactivation

ontumormetabolismisstronglydepen-

dentonthedifferentiationstateofthetu-

morcells.Uncoveringthemolecularbasis

forthisspecificitywithregardtodifferen-

tialoncogenicreprogrammingofcellular

metabolismwillbeacriticalnextstepin

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