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.; Heininger, S. C. J.; Ather, J. L.; Sarausky, H.; Stephenson, D.; Reisz, J. A.; D'Alessandro, A.; Majumdar, D.; Janssen-Heininger, Y. M. W.; Poynter, M. E.; Seward, D. J.; Toth, M. J.

doi:10.1101/2024.09.27.615385

bioRxiv · 10.1101/2024.09.27.615385

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.·Heininger, S. C. J.·Ather, J. L.·Sarausky, H.·Stephenson, D.·Reisz, J. A.·D'Alessandro, A.·Majumdar, D.·Janssen-Heininger, Y. M. W.·Poynter, M. E.·Seward, D. J.·Toth, M. J.

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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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Snoke, D. B., van der Velden, J. L., Bellefleur, E. R., Dearborn, J. S., Lenahan, S. M., Heininger, S. C. J., Ather, J. L., Sarausky, H., Stephenson, D., Reisz, J. A., D'Alessandro, A., Majumdar, D., Janssen-Heininger, Y. M. W., Poynter, M. E., Seward, D. J., Toth, M. J.. 2024-09-30. Novel preclinical model of human lung cancer cachexia. https://doi.org/10.1101/2024.09.27.615385

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