Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue 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, we generated tamoxifen-inducible, epithelial cell specific Kras ^G12D/+ ( G12D ) mice. G12D mice develop CC over a protracted time course and phenocopy tissue, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. CC in G12D mice is characterized by early loss of adipose tissue, a phenotype confirmed in a large cohort of patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.