Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice
Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice
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DOI：
10.1038/s41591-020-0945-x
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发表时间：
2020-07-13
期刊：
影响因子：
82.9
通讯作者：
Allan, Bernard B.
中科院分区：
文献类型：
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作者：
Suriben, Rowena;Chen, Michael;Allan, Bernard B.
癌症恶病质是一种非常普遍的疾病，与生活质量差和生存率降低有关(1)。肿瘤诱导的内分泌、免疫和神经系统的紊乱会导致脂肪组织和骨骼肌的厌食和分解代谢变化，这是癌症恶病质的标志（2-4）。然而，导致恶病质的分子机制仍然不清楚，目前还没有批准的药物治疗这种疾病。循环生长分化因子15 （GDF15）的升高与癌症患者的恶病质和生存率降低相关（5-8），最近研究人员描述了脑干神经元中GDNF家族受体α样(GFRAL)-Ret原癌基因（RET）信号复合物介导GDF15诱导的小鼠体重减轻（9-12）。在这里，我们报道了一种治疗性拮抗单克隆抗体3P10，它靶向GFRAL，并通过阻止gdf15驱动的RET与GFRAL在细胞表面的相互作用来抑制RET信号传导。即使在卡路里限制的条件下，用3P10治疗也能逆转肿瘤小鼠过度的脂质氧化，并预防癌症恶病质。在机制上，GFRAL-RET通路的激活诱导了脂肪组织中参与脂质代谢的基因的表达，外周化学交感神经切除术和脂肪甘油三酯脂肪酶的丧失都可以保护小鼠免受gdf15诱导的体重减轻。这些数据揭示了外周交感神经轴，GDF15通过该轴在脂肪组织中引起独立于厌食症的脂溶反应，导致荷瘤小鼠脂肪和肌肉质量和功能减少。临床前肿瘤模型中GFRAL-RET信号的药理抑制支持逆转癌症患者gdf15依赖性恶病质的治疗潜力。
Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival(1). Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia(2-4). However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer(5-8), and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described(9-12). Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.Pharmacological inhibition of GFRAL-RET signaling in preclinical tumor models supports the therapeutic potential for reversing GDF15-dependent cachexia in people with cancer.