Oncogenic stress-induced Netrin reprograms systemic metabolism as a humoral inter-organ molecule in Drosophila
Cancer exerts pleiotropic, systemic effects on organisms. Health of organisms with cancer deteriorates, eventually leading to organismal death. How cancer induces systemic effects on remote organs and the organism itself still remains elusive. Here we describe a role for NetrinB (NetB), a protein with a particularly well-characterized role as a tissue-level axon guidance cue (Bradford, Cole, & Cooper, 2009; Kennedy, 2000; Serafini et al., 1996), in mediating oncogenic stress-induced organismal, metabolic reprogramming as a systemic humoral factor. Ras-induced dysplasia upregulates and secretes NetB. Inhibition of either NetB from the transformed tissue or its receptor in the fat body suppresses oncogenic stress-induced organismal death. Mechanistically, NetB from the dysplastic tissue remotely suppresses carnitine biosynthesis, which is critical for acetyl-CoA generation and systemic metabolism, in the fat body. Supplementation of carnitine or acetyl-CoA inhibits oncogenic stress-induced organismal death. This is the first identification, to our knowledge, of a role for the Netrin molecule, which has been studied extensively for its role within tissues, in humorally mediating systemic effects of local oncogenic stress on remote organs and organismal metabolism.