Snoke Deena B, van der Velden Jos L, Bellafleur Emma R, Dearborn Jacob S, Lenahan Sean M, Beal Alexandra E, Aboushousha Reem, Heininger Skyler C J, Ather Jennifer L, Mank Madeleine M, Sarausky Hailey, Stephenson Daniel, Reisz Julie A, D'Alessandro Angelo, Majumdar Devdoot, Ahern Thomas P, Xu Kaiwen, Sandler Kim L, Landman Bennett A, Janssen-Heininger Yvonne M W, Poynter Matthew E, Seward David J, Toth Michael J
Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
Department of University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT.
bioRxiv. 2025 Jul 1:2024.09.27.615385. doi: 10.1101/2024.09.27.615385.
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 () mice. mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. 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, mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC.
癌症恶病质（CC）是一种骨骼肌和脂肪消耗的综合征，它会降低对治疗的反应性并增加死亡率。目前尚无针对CC的获批治疗方法，这可能与临床前模型和人类CC之间的不一致有关。为了满足对临床相关的肺CC模型的需求，我们构建了可诱导的、肺上皮细胞特异性的（）小鼠。小鼠在较长的时间进程中发展为CC，并模拟人类肺CC的组织和肿瘤、细胞、突变、转录组和代谢特征。小鼠表现出脂肪的早期流失，这一表型在众多CC模型中都很明显，并且在肺癌患者中也存在。肿瘤释放的因子促进脂肪细胞脂解，这是CC中脂肪消耗的驱动因素，并且脂肪消耗与肿瘤负担呈负相关。因此，小鼠模拟了人类肺CC的关键特征，并突出了早期肿瘤对脂肪组织的代谢重编程在CC中的作用。
