Oncogenic stress‐induced Netrin is a humoral signaling molecule that reprograms systemic metabolism in Drosophila

Cancer exerts pleiotropic, systemic effects on organisms, leading to health deterioration and eventually 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, in mediating oncogenic stress‐induced organismal, metabolic reprogramming as a systemic humoral factor. In Drosophila , Ras‐induced dysplastic cells upregulate and secrete NetB. Inhibition of either NetB from the transformed tissue or its receptor in the fat body suppresses oncogenic stress‐induced organismal death. NetB from the dysplastic tissue remotely suppresses carnitine biosynthesis in the fat body, which is critical for acetyl‐CoA generation and systemic metabolism. Supplementation of carnitine or acetyl‐CoA ameliorates organismal health under oncogenic stress. 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. Synopsis NetrinB is a secreted protein that acts as a regulator of cell migration and an axon guidance cue. The current study identifies a role for NetB as a humoral signaling molecule that mediates systemic effects of local oncogenic stress on organismal metabolism in Drosophila . Ras‐induced dysplastic cells upregulate and secrete NetrinB. Inhibition of either NetrinB from the transformed tissue or its receptor in the fat body suppresses oncogenic stress‐induced organismal death. NetrinB from the dysplastic tissue suppresses carnitine biosynthesis in the fat body. Supplementation of carnitine or acetyl‐CoA improves fly survival under oncogenic stress. Graphical Abstract Ras‐induced tumors in Drosophila reduce organismal fitness by Netrin secretion‐dependent suppression of carnitine biosynthesis in the fat body.