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RRC ID 83855
著者 Liu Y, Dantas E, Ferrer M, Miao T, Qadiri M, Liu Y, Comjean A, Davidson EE, Perrier T, Ahmed T, Hu Y, Goncalves MD, Janowitz T, Perrimon N.
タイトル Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
ジャーナル Nat Metab
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.
巻・号 7(4)
ページ 823-841
公開日 2025-4-1
DOI 10.1038/s42255-025-01265-2
PII 10.1038/s42255-025-01265-2
PMID 40275022
PMC PMC12021660
MeSH Animals Cachexia* / etiology Cachexia* / genetics Cachexia* / metabolism Disease Models, Animal Drosophila Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Gluconeogenesis* / genetics Humans Liver* / metabolism Mice Neoplasms* / complications Neoplasms* / metabolism Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / genetics Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / metabolism Up-Regulation
リソース情報
ショウジョウバエ 15009R-3