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

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 (April 2025) Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice. Nature Metabolism, 7 (4). pp. 823-841. ISSN 2522-5812 (Public Dataset)

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Abstract

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.

Item Type: Paper
Subjects: diseases & disorders
diseases & disorders > nutritional and metabolic diseases
organism description > animal
diseases & disorders > nutritional and metabolic diseases > cachexia
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
organism description > animal > mammal > rodent
CSHL Authors:
Communities: CSHL labs > Borniger lab
CSHL labs > Janowitz lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: April 2025
Date Deposited: 25 Apr 2025 16:19
Last Modified: 25 Apr 2025 16:19
Related URLs:
Dataset ID:
URI: https://repository.cshl.edu/id/eprint/41858

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