Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice
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.
Authors
- Marcus DaSilva Goncalves (ORCID: https://orcid.org/0000-0002-0784-9248)
- Yanhui Hu (ORCID: https://orcid.org/0000-0003-1494-1402)
- Ting Miao (ORCID: https://orcid.org/0000-0002-0634-7377)
- Emma E. Davidson (ORCID: https://orcid.org/0000-0003-4006-2508)
- Ezequiel Dantas (ORCID: https://orcid.org/0000-0003-4934-4632)
- Tobias Janowitz (ORCID: https://orcid.org/0000-0002-7820-3727)
- Norbert Perrimon (ORCID: https://orcid.org/0000-0001-7542-472X)
- Aram Comjean (ORCID: https://orcid.org/0000-0003-4125-0703)
- Miriam Ferrer (ORCID: https://orcid.org/0000-0002-5589-975X)
- Tiffany Perrier (ORCID: https://orcid.org/0000-0001-7688-076X)
- Ying Liu (ORCID: https://orcid.org/0000-0002-6419-1980)
- Tanvir Ahmed (ORCID: https://orcid.org/0000-0002-6748-2441)
- Yifang Liu (ORCID: https://orcid.org/0000-0002-5382-640X)
- Mujeeb Qadiri (ORCID: https://orcid.org/0009-0006-9697-6447)
Institutions
- Northwell Health (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Cornell University (US)
- Cold Spring Harbor Laboratory (US)
- Center for Human Genetics (US)
- Boston VA Research Institute (US)
- Weill Cornell Medicine (US)
- The Ohio State University (US)
- New York University (US)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1038/s42255-025-01265-2
- Citations
- 19
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 15.31
Funders
- Charles A. King Trust
- Cancer Research UK
- National Cancer Institute