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Full-Body Transcriptome Uncovers Hepatic Gluconeogenesis and PDK3 Upregulation as a Key Driver of Cancer Cachexia

ABSTRACT: Cachexia, a severe wasting syndrome characterized by tumor-induced metabolic dysregulation, is a leading cause of death in cancer patients, yet its underlying mechanisms remain poorly understood. We performed a longitudinal full-body single-nuclei resolution transcriptome analysis in a Drosophila model of cancer cachexia to capture interorgan dysregulations. Our study revealed that the tumor-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 regulation of their orthologs Pck1 and Pdk3 by IL-6/JAK-STAT signaling. Elevated expression of these genes in fly, mouse, and patients correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a novel mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumor-induced metabolic disruptions and identifies new therapeutic targets to mitigate cachexia in cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE286259 | GEO | 2025/02/13

REPOSITORIES: GEO

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Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.

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Full-Body Transcriptome Uncovers Hepatic Gluconeogenesis and PDK3 Upregulation as a Key Driver of Cancer Cachexia

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