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<p>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 <i>Drosophila</i> model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of <i>Pepck1</i> and <i>Pdk</i>, 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 <i>Pck1</i> and <i>Pdk3</i> expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of <i>Pdk3</i> 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.</p>

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Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • Ying Liu,
  • Ezequiel Dantas,
  • Miriam Ferrer,
  • Ting Miao,
  • Mujeeb Qadiri,
  • Yifang Liu,
  • Aram Comjean,
  • Emma E. Davidson,
  • Tiffany Perrier,
  • Tanvir Ahmed,
  • Yanhui Hu,
  • Marcus D. Goncalves,
  • Tobias Janowitz,
  • Norbert Perrimon

摘要

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.