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.

癌症可对生物体产生多效性全身性影响，导致健康状况恶化，最终引发生物体死亡。目前，癌症如何诱发远端器官及生物体本身的全身性影响，其具体机制仍未明确。本研究揭示了NetrinB（简称NetB）的全新功能：作为一类系统性体液因子，该蛋白可介导致癌应激引发的全身性代谢重编程；而其作为组织层面轴突导向信号的经典功能此前已得到充分研究与明确表征。在果蝇模型中，Ras诱导的异常增生细胞会上调NetB的表达并分泌该蛋白。抑制转化组织分泌的NetB，或是阻断脂肪体中NetB受体的功能，均可抑制致癌应激引发的生物体死亡。异常增生组织分泌的NetB可远程抑制脂肪体内的肉碱生物合成，而该过程对于乙酰辅酶A的生成及全身性代谢均至关重要。补充肉碱或乙酰辅酶A，可改善致癌应激状态下生物体的健康状况。据我们所知，本研究首次证实了Netrin家族分子的全新功能——此前学界已对该家族分子在组织内部的功能开展了广泛研究，而本研究揭示其可通过体液途径，介导局部致癌应激对远端器官及生物体代谢产生的全身性影响。