Early adipose tissue wasting in a preclinical model of human lung cancer cachexia
Cancer cachexia (CC), a syndrome of skeletal muscle and adipose wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between preclinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell-specific Kras<sup>G12D/+</sup> (G12D) mice. G12D mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. G12D mice demonstrate early loss of adipose, a phenotype that was apparent across numerous models of CC and translates to patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in CC, and adipose wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC.
Authors
- Hailey Sarausky
- Julie A. Reisz (ORCID: https://orcid.org/0000-0002-7296-4963)
- Madeleine M. Mank (ORCID: https://orcid.org/0000-0002-0617-4736)
- Yvonne Janssen‐Heininger (ORCID: https://orcid.org/0000-0002-2735-8745)
- Reem Aboushousha (ORCID: https://orcid.org/0000-0003-2284-2180)
- Michael J. Toth (ORCID: https://orcid.org/0000-0003-0668-1911)
- David J. Seward (ORCID: https://orcid.org/0000-0001-5821-6187)
- Kaiwen Xu (ORCID: https://orcid.org/0000-0002-2664-255X)
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- Kim Lori Sandler (ORCID: https://orcid.org/0000-0003-2989-248X)
- Allison M. Beal (ORCID: https://orcid.org/0000-0001-5600-3380)
- Matthew E. Poynter (ORCID: https://orcid.org/0000-0002-7578-4570)
- Deena B. Snoke (ORCID: https://orcid.org/0000-0003-2189-9441)
- Jennifer L. Ather (ORCID: https://orcid.org/0000-0003-0484-5599)
- Daniel Stephenson (ORCID: https://orcid.org/0000-0002-5698-3400)
- Bennett A. Landman (ORCID: https://orcid.org/0000-0001-5733-2127)
- Jacob Dearborn (ORCID: https://orcid.org/0000-0001-8894-1574)
- Thomas P. Ahern (ORCID: https://orcid.org/0000-0003-0440-8727)
- Sean Lenahan (ORCID: https://orcid.org/0000-0003-3222-970X)
- Jos van der Velden (ORCID: https://orcid.org/0000-0002-2451-3180)
- Devdoot Majumdar (ORCID: https://orcid.org/0000-0002-2541-3851)
- Skyler C. J. Heininger
- Emma R. Bellafleur
Institutions
- University of Vermont (US)
- University of Colorado Anschutz Medical Campus (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116278
- Primary Topic
- Nutrition and Health in Aging
- Type
- article
- Field-Weighted Citation Impact
- 0.00