Background: Cancer cachexia (CC), a syndrome characterized by skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases morbidity and mortality. Lung cancer is the leading cause of cancer-related deaths worldwide with a large percentage of patients experiencing CC. Despite a wealth of mechanistic data on CC, there are no approved treatments, which may relate to the fact that many pre-clinical models do not reproduce the pathophysiological features of human CC. Methods: We generated tamoxifen-inducible, club cell specific KrasG12D/+ (G12D) mice to model lung cancer and investigated the development and progression of CC by assessing tumor characteristics, time course of CC, adipose and skeletal muscle tissue sizes and transcriptional profiles, and circulating inflammatory cytokines.Results: Induction of the KrasG12D allele caused adenocarcinomas in the terminal bronchioles, which were evident at initiation of weight loss (10.5 +/- 1.1% lung volume at 6 weeks). Weight loss in G12D mice averaged 15% over 12 weeks, with loss of both adipose (-72%-85% vs. WT) and skeletal muscle tissue mass (-17-23% vs. WT) and tissue transcriptional profiles consistent with CC. Exploiting the protracted time course of this model, we found that early during CC adipose tissue, but not skeletal muscle, mass and cell size were reduced by greater than 50% in G12D mice compared to WT, a result that was confirmed in a more rapidly progressive, Kras driven model of lung CC containing Stk11 loss of function (KrasG12D/+/Stk11-/-) where depletion of adipose depots (>50% vs WT) occurred over 3.5 weeks. G12D mice showed circulating metabolomic markers of increased fat mobilization/utilization, including elevated glycerol levels (+20% vs. WT), which was also apparent in patients with lung cancer (+79% vs. non-cancer controls). Additionally, 3T3-L1 adipocytes treated with conditioned media (CM) from tumor organoids developed from G12D mice caused a 3-fold increase in glycerol and 2-3 fold increase in pro-inflammatory cytokine release compared to CM from WT lung tissue. Conclusions: G12D mice develop CC over a more protracted period and phenocopy tumor and tissue cellular, mutational, transcriptomic, and metabolic characteristics relevant to human lung CC. Additionally, G12D mice show early loss of adipose tissue, and factors released from G12D lung tumor organoids produce metabolic adaptations in vitro that promote adipose tissue wasting. Thus, G12D mice model features of human lung CC and may advance the study of the pathoetiology and treatment of CC.
