Year: 2024
Type: preprint
Abstract: Summary 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 Kras G12D/+ ( 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
Authors: Deena B. Snoke, Jos L. van der Velden, Emma R. Bellafleur, Jacob S. Dearborn, Sean M. Lenahan, Alexandra E. Beal, Reem Aboushousha, Skyler C. J. Heininger, Jennifer L. Ather, Madeleine M. Mank, Hailey Sarausky, Daniel Stephenson, Julie A. Reisz, Angelo D’Alessandro, Devdoot Majumdar, Thomas P. Ahern, Kaiwen Xu, Kim L. Sandler, Bennett A. Landman, Yvonne M.W. Janssen-Heininger, Matthew E. Poynter, David J. Seward, Michael J. Toth
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1565180698, Skeletal Muscle Atrophy and Dysfunction in Human Cancer, G3298087253, G5029337574, STK11 loss of function and anti-PD-1 therapy resistance in KRAS-driven lung adenocarcinoma, Development of a clinically relevant mouse model of lung cancer cachexia to study pathoetiology and therapeutic strategies, G9000048075, G9000193132, G9000241227, G9000259301, G9000301509, Northern New England Clinical and Translational Research Network, Michigan Nutrition Obesity Research Center, Novel Integrative Approach for the Early Detection of Lung Cancer using Repeated Measures, G9001225491
OpenAlex ID: W4402989158