Livingston Patrick D, Labbate Bonaldo Ana Luiza, Jamnick Nicholas A, Weinzierl Natalia M, Gammon Caleb J, Callaway Chandler S, Lee Schuyler, Gao Bifeng, Goodspeed Andrew, Carvalho Robson F, Young Christian D, Orlicky David J, Adams Douglas J, Novinger Leah J, Bonetto Andrea
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.
Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
Am J Physiol Cell Physiol. 2025 Aug 1;329(2):C646-C658. doi: 10.1152/ajpcell.00374.2025. Epub 2025 Jul 21.
Head and neck cancer (HNC) accounts for ∼4% of all cancers but causes ∼15,000 deaths annually in the United States. Over 40% of HNC patients present with cachexia, a severe comorbidity associated with skeletal muscle defects, worsened treatment response, and poor outcomes. The mechanisms behind HNC cachexia remain unclear, partly due to limited small animal models. This study characterizes functional and molecular features of cachexia in a novel preclinical model using tobacco-induced B0092 oral squamous cell carcinoma in C57BL/6J mice. C2C12 myotubes were exposed to various concentrations of B0092 conditioned media (CM) to assess effects on myotube diameter and expression of muscle-specific ubiquitin ligases (MuRF-1 and atrogin-1). C57BL/6J male and female mice were implanted with B0092 cells (5 × 10 cells) to investigate musculoskeletal effects of HNC. RNA sequencing of muscle identified gene signatures associated with cachexia. Myotubes treated with B0092 CM showed atrophy already at 25% CM (-21%, < 0.01), along with elevated MuRF-1 (+81%, < 0.05) and atrogin-1 (+27%, < 0.05). B0092 tumor growth in male mice led to muscle atrophy, reduced strength (-36%, < 0.001), and lower bone mineral density (-8%, < 0.01). Muscle atrophy correlated with increased MuRF-1 (+1.96-fold, < 0.05) and atrogin-1 (+1.97-fold, < 0.05). Female mice exhibited moderate cachexia despite similar tumor size. RNA sequencing of muscle in male B0092 hosts revealed mitochondrial dysfunction and upregulation of proteasome- and translation-related pathways, supporting a shift toward protein degradation and impaired energy metabolism. These findings suggest that B0092-bearing mice are valuable to uncover novel molecular pathways and potential therapeutic targets for HNC cachexia. This study introduces a novel preclinical model for head and neck cancer (HNC) cachexia using B0092 oral squamous cell carcinoma in C57BL/6J mice. Key findings include muscle atrophy, systemic musculoskeletal effects, and critical gene signatures associated with skeletal muscle wasting. These insights pave the way for potential therapeutic targets to mitigate cachexia in patients with HNC, offering a promising avenue for improving patient outcomes.
头颈癌（HNC）占所有癌症的约4%，但在美国每年导致约15000人死亡。超过40%的HNC患者存在恶病质，这是一种与骨骼肌缺陷、治疗反应恶化和预后不良相关的严重合并症。HNC恶病质背后的机制仍不清楚，部分原因是小动物模型有限。本研究在一种新的临床前模型中，利用烟草诱导的C57BL/6J小鼠B0092口腔鳞状细胞癌，对恶病质的功能和分子特征进行了表征。将C2C12肌管暴露于不同浓度的B0092条件培养基（CM）中，以评估对肌管直径和肌肉特异性泛素连接酶（MuRF-1和atrogin-1）表达的影响。将B0092细胞（5×10个细胞）植入C57BL/6J雄性和雌性小鼠体内，以研究HNC对肌肉骨骼的影响。对肌肉进行RNA测序，确定与恶病质相关的基因特征。用B0092 CM处理的肌管在25%CM时就已出现萎缩（-21%，P<0.01），同时MuRF-1升高（+81%，P<0.05）和atrogin-1升高（+27%，P<0.05）。雄性小鼠体内B0092肿瘤生长导致肌肉萎缩、力量降低（-36%，P<0.001）和骨矿物质密度降低（-8%，P<0.01）。肌肉萎缩与MuRF-1升高（+1.96倍，P<0.05）和atrogin-1升高（+1.97倍，P<0.05）相关。尽管肿瘤大小相似，但雌性小鼠表现出中度恶病质。对雄性B0092宿主的肌肉进行RNA测序，发现线粒体功能障碍以及蛋白酶体和翻译相关途径上调，支持向蛋白质降解和能量代谢受损的转变。这些发现表明，携带B0092的小鼠对于揭示HNC恶病质的新分子途径和潜在治疗靶点具有重要价值。本研究引入了一种利用C57BL/6J小鼠B0092口腔鳞状细胞癌建立的新的头颈癌（HNC）恶病质临床前模型。主要发现包括肌肉萎缩、全身性肌肉骨骼影响以及与骨骼肌消耗相关的关键基因特征。这些见解为减轻HNC患者恶病质的潜在治疗靶点铺平了道路，为改善患者预后提供了一条有希望的途径。
