(P13-038-23) Early Adipose Tissue Wasting in a Novel Model of Lung Cancer Cachexia

Objectives: Most lung cancer patients exhibit cancer cachexia (CC), a syndrome of skeletal muscle and fat tissue wasting. No effective therapies for CC have been identified, in part because pathoetiological mechanisms contributing to disease progression are difficult to capture in currently available, rapidly progressing preclinical models. Thus, the goal of this work was to develop and characterize a mouse model of lung CC that better aligns with the clinical syndrome.

Methods: Club-cell specific tamoxifen-inducible Kras^G12D/+ mice were induced at 4-5 months of age and body weight was monitored over a 12-week period. At 6- and 12-weeks post-induction, tissues were weighed or prepared for histology to measure cell size and tumor burden, and blood was collected for measurement of circulating cytokines. We generated lung organoids from WT and Kras^G12D mice and isolated their RNA for RNAseq. Differentiated 3T3L1 adipocytes and C2C12 myotubes were treated with lung organoid conditioned medium (CM) to model the effects of lung tumor-derived factors on peripheral tissues.

Results: Kras^G12D mice were characterized by ~15% body weight loss over 12 weeks, yielding a rate of body weight loss (~1.9%/week) that corresponds favorably with human CC patients (~1%/week) and is much slower than currently used models (5-10%/week). Body weight loss was accompanied by a marked depletion in adipose tissue mass. At 6 weeks post-induction, when animals are pre-cachectic ( < 5% body weight loss), we observed loss of fat pad weight and ~50% lower adipocyte cross-sectional area, while muscle weights were unaltered. Additionally, CM from Kras^G12D lung organoids elicited glycerol and IL-6 release from cultured adipocytes when compared to CM from WT organoids.

Conclusions: These findings suggest that lung epithelial-specific, inducible Kras^G12D mice better model the time course of CC development and progression in humans compared to currently available lung cancer models and highlight fat loss as an early pathological event in CC that may be mediated by tumor-derived factors.

Funding Sources: National Institutes of Health, Vermont Lung Center Lung Biology Training Program, University of Vermont Cancer Center