Early adipose tissue wasting in a preclinicl 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 pre-clinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell specific KrasG12D/+ (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. White adipose tissues were excised and lung organoids isolated and cultured from the lungs of Scgb1a1-CreER-TM-KrasLSL-G12D/+ (G12D) or wild-type Scgb1a1-CreERTM mice 3 and 6 weeks after tamoxifen administration. Organoid and white adipose tissue RNA was isolated from G12D or WT mice and prepared and RNAseq profiling carried out.