Letterhttps://doi.org/10.1038/s41586-018-0697-7AutophagymaintainstumourgrowththroughcirculatingarginineLauraPoillet-Perez1,XiaoqiXie1,LeZhan1,YangYang1,DanielW.Sharp1,ZhixianSherrieHu1,XiaoyangSu1,2,AnuragMaganti1,CherryJiang1,WenyunLu3,HaiyanZheng4,MarcusW.Bosenberg5,JaniceM.Mehnert1,6,JessieYanxiangGuo1,2,7,edmundLattime1,8,JoshuaD.rabinowitz1,3&eileenWhite1,9*Autophagycapturesintracellularcomponentsanddeliversthemtolysosomes,wheretheyaredegradedandrecycledtosustainmetabolismandtoenablesurvivalduringstarvation1–5.Acute,whole-bodydeletionoftheessentialautophagygeneAtg7inadultmicecausesasystemicmetabolicdefectthatmanifestsasstarvationintoleranceandgraduallossofwhiteadiposetissue,liverglycogenandmusclemass1.Cancercellsalsobenefitfromautophagy.Deletionofessentialautophagygenesimpairsthemetabolism,proliferation,survivalandmalignancyofspontaneoustumoursinmodelsofautochthonouscancer6,7.Acute,systemicdeletionofAtg7oracute,systemicexpressionofadominant-negativeATG4binmiceinducesgreaterregressionofKRAS-drivencancersthandoestumour-specificautophagydeletion,whichsuggeststhathostautophagypromotestumourgrowth1,8.Hereweshowthathost-specificdeletionofAtg7impairsthegrowthofmultipleallograftedtumours,althoughnotalltumourlinesweresensitivetohostautophagystatus.Lossofautophagyinthehostwasassociatedwithareductionincirculatingarginine,andthesensitivetumourcelllineswerearginineauxotrophsowingtothelackofexpressionoftheenzymeargininosuccinatesynthase1.Serumproteomicanalysisidentifiedthearginine-degradingenzymearginaseI(ARG1)inthecirculationofAtg7-deficienthosts,andinvivoargininemetabolictracingdemonstratedthatserumargininewasdegradedtoornithine.ARG1ispredominantlyexpressedintheliverandcanbereleasedfromhepatocytesintothecirculation.Liver-specificdeletionofAtg7producedcirculatingARG1,andreducedbothserumarginineandtumourgrowth.DeletionofAtg5inthehostsimilarlyregulatedcirculatingarginineandsuppressedtumorigenesis,whichdemonstratesthatthisphenotypeisspecifictoautophagyfunctionratherthantod...
