bioRxiv : the preprint server for biology · 2025
Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Snoke Deena B, van der Velden Jos L, Bellafleur Emma R, Dearborn Jacob S, Lenahan Sean M, Beal Alexandra E, Aboushousha Reem, Heininger Skyler C J, Ather Jennifer L, Mank Madeleine M, Sarausky Hailey, Stephenson Daniel, Reisz Julie A, D'Alessandro Angelo, Majumdar Devdoot, Ahern Thomas P, Xu Kaiwen, Sandler Kim L, Landman Bennett A, Janssen-Heininger Yvonne M W, Poynter Matthew E, Seward David J, Toth Michael J
Аннотация
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 pre-clinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell specific Kras G12D/+ (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.