Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia
Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.
Authors
- John W. Garrett (ORCID: https://orcid.org/0000-0002-8152-736X)
- Rachel J. Fenske (ORCID: https://orcid.org/0000-0002-5417-0780)
- Andrea Galmozzi (ORCID: https://orcid.org/0000-0002-9411-7327)
- Kaitlin A. Kressin (ORCID: https://orcid.org/0000-0002-2266-5340)
- Jevin Lortie (ORCID: https://orcid.org/0000-0001-9647-2579)
- Matías Fabregat (ORCID: https://orcid.org/0000-0002-8248-5464)
- Adam J. Kuchnia (ORCID: https://orcid.org/0000-0002-3418-0965)
- Marina Pasca di Magliano (ORCID: https://orcid.org/0000-0001-9632-9035)
- Annie Jen (ORCID: https://orcid.org/0000-0001-5569-8387)
- Perry Joseph Pickhardt (ORCID: https://orcid.org/0000-0002-5534-8202)
- Costas Andreas Lyssiotis (ORCID: https://orcid.org/0000-0001-9309-6141)
- Joshua J. Coon (ORCID: https://orcid.org/0000-0002-0004-8253)
- Lingjun Li (ORCID: https://orcid.org/0000-0003-0056-3869)
- Caroline M. Alexander (ORCID: https://orcid.org/0000-0002-7830-8043)
- Katherine Overmeyer
- Carmen Kaminsky
- Julia K. Hansen
- Alexander Nassar (ORCID: https://orcid.org/0009-0000-2215-931X)
- Lucia Cilloni
Institutions
- University of Wisconsin–Madison (US)
- University of Michigan (US)
- Morgridge Institute for Research (US)
- Quantitative BioSciences (US)
- University of Wisconsin Carbone Cancer Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-03
- DOI
- https://doi.org/10.64898/2025.12.01.691597
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00