Oncogenic stress-induced Netrin reprograms systemic metabolism as a humoral inter-organ molecule in Drosophila
DOI:
https://doi.org/10.51094/jxiv.114Keywords:
Netrin, oncogenic stress, DrosophilaAbstract
Cancer exerts pleiotropic, systemic effects on organisms (Bilder, Ong, Hsi, Adiga, & Kim, 2021; Hiam-Galvez, Allen, & Spitzer, 2021). 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.
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Morihiro Okada
Tomomi Takano
Yuko Ikegawa
Hanna Ciesielski
Hiroshi Nishida
Sa Kan Yoo
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