Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia
Snoke, D. B.; van der Velden, J. L.; Bellefleur, E. R.; Dearborn, J. S.; Lenahan, S. M.; Beal, A. E.; Aboushousha, R.; Heininger, S. C. J.; Ather, J. L.; Mank, M. M.; Sarausky, H.; Stephenson, D.; Reisz, J. A.; D'Alessandro, A.; Majumdar, D.; Ahern, T. P.; Sandler, K. L.; Landman, B. A.; Janssen-Heininger, Y. M. W.; Poynter, M. E.; Seward, D. J.; Toth, M. J.
Show abstract
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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/615385v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@66d87dorg.highwire.dtl.DTLVardef@f1cb4org.highwire.dtl.DTLVardef@2580f1org.highwire.dtl.DTLVardef@3463d5_HPS_FORMAT_FIGEXP M_FIG C_FIG
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