Liu Ying, Dantas Ezequiel, Ferrer Miriam, Miao Ting, Qadiri Mujeeb, Liu Yifang, Comjean Aram, Davidson Emma E, Perrier Tiffany, Ahmed Tanvir, Hu Yanhui, Goncalves Marcus D, Janowitz Tobias, Perrimon Norbert
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
Nat Metab. 2025 Apr;7(4):823-841. doi: 10.1038/s42255-025-01265-2. Epub 2025 Apr 16.
Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
恶病质是一种以肿瘤诱导的代谢失调为特征的严重消瘦综合征，是癌症患者死亡的主要原因，但其潜在机制仍知之甚少。在这里，我们表明，在果蝇癌症恶病质模型中进行的纵向全身单核分辨率转录组分析揭示了器官间的失调。我们的研究表明，肿瘤分泌的白细胞介素样细胞因子Upd3诱导脂肪体中糖异生的关键调节因子Pepck1和Pdk的表达，破坏葡萄糖代谢并导致恶病质。同样，在小鼠癌症恶病质模型中，我们观察到肝脏中IL-6-JAK-STAT信号介导的Pck1和Pdk3表达的诱导。这些基因在果蝇、小鼠和人类中的表达增加与预后不良相关，而Pdk3的肝脏表达是导致癌症恶病质代谢功能障碍的一种先前未知的机制。这项研究突出了肿瘤诱导的代谢紊乱的保守性质，并确定了减轻癌症患者恶病质的潜在治疗靶点。
