Tumor-Stroma Interactions Reprogram Metabolism in Human Anaplastic Thyroid Cancer Cells

FOZZATTI L; ALAMINO VA; GIUSIANO L; STEMPIN C; DONADIO AC; PELLIZAS CG

Victoria

Congreso; 87th Annual Meeting of the American Thyroid Association; 2017

American Thyroid Association (ATA)

Thyroidcanceristhemostcommonendocrinemalignancy,withrisingincidence.Anaplasticthyroidcancer(ATC)isoneofthemostaggressivetumors.Characterizedbyitsundifferentiatedcells,itspreadsquicklytodistantorgansanddoesnotrespondwelltotherapy.Itiswellknownthatgeneticabnormalitiesinoncogenesand/ortumorsuppressorgenespromotetumorigene-sis.Emergingevidences,however,haveshownthattumorstromahasacrucialinfluenceoncancerdevelopmentandprogressionaswell.Dysregulatedmetabolismwithinthetumorstromaiscrit-icaltotheprocessoftumorigenesis,howeverstudiesanalyzingtheroleofmulticompartmentmetabolisminATCarelackingToinvestigatewhethertheinteractionofATCcells-fibroblasts(maincomponentoftumorstroma)reprogramstheircellularmetabolism,weusedan invitro ATCcell(8505candKTC-2cells)-fibroblast(MRC-5cells)transwellco-culturesystemandmeasuredavarietyofmetabolicparametersbyflowcytometry,RT-qPCR,ELISAandWesternblotanalysis.Weshowedthatduringco-cultures,fibroblastsincreasedreactiveoxygenspecies(ROS)production,thetranscriptandsecretionoftheinflamma-torycytokineIL6,themRNAexpressionoftwoglycolyticen-zymes:lactatedehydrogenaseA(LDHA)andenolase1(ENO1)andthemRNAandproteinlevelsofglucosetransporter1(GLUT1).Conversely,co-culturedATCcellsshowedreductioninGLUT1,ENO1andLDHAexpression.HighROSlevelsin-duceoxidativestressthatmaytriggertheactivationofhypoxia-induciblefactor1a (HIF-1a),leadingtoinflammationandgly-colysis.Therefore,weanalyzeditsmRNAexpressionintheco-cultures.Interestingly,weregisteredanincreaseofmRNAlevelsofHIF-1a infibroblastsco-culturedwiththyroidcells.Accord-ingly,weobservedasignificantriseofthistranscriptionfactorinthetumorthyroidcellsco-culturedwithfibroblasts.Ourfindingsprovide invitro evidencesofareprogrammedmetabolismbystromal-thyroidtumorcellsinteractions,suggestingtheirpar-ticipationinATCdevelopmentandprogression.Animprovedunderstandingofthemolecularbasisoftumor-stromacommu-nicationsmayenableidentificationandtargetingoftumor-supportivemechanisms.