Murine pancreatic tumors induce pathological remodeling of muscles critical to chewing and swallowing [RNA-seq]

Cancer cachexia is a debilitating syndrome defined by involuntary weight loss due to loss of muscle mass, with or without loss of fat mass. Cachexia is particularly prevalent in pancreatic cancer, affecting up to 70% of patients at diagnosis, and is associated with reduced physical function, impaired treatment tolerance, and worsened survival. Skeletal muscle, including muscles involved in respiration and locomotion, exhibit extensive pathological remodeling in cachexia, including myofiber atrophy and transcriptional reprogramming. Whether muscles that are critical to chewing and swallowing respond similarly remains unknown. To address this gap, we collected masseter (chewing) and digastric (swallowing) muscles from cachectic mice bearing orthotopic KPC pancreatic tumors (n=8) and cancer-free Sham controls (n=8). Hematoxylin and eosin staining revealed increased mononuclear cell content, centralized nuclei, and expanded interstitial spaces in both muscles of KPC mice. Myofiber cross-sectional area was reduced by 42% in the masseter and 23% in the digastric. RNA sequencing revealed distinct transcriptional responses between these muscles. The masseter muscle showed enrichment of catabolic signaling pathways, including proteolytic and stress-response programs, alongside downregulation of extracellular matrix and growth-related programs. In contrast, the digastric muscle exhibited robust upregulation of immune and inflammatory pathways, including innate and adaptive immune signaling, with minimal overlap between muscles. Collectively, these findings demonstrate that pancreatic cancer drives pathological remodeling and atrophy in muscles central to chewing and swallowing while eliciting distinct, muscle-specific transcriptional responses, changes that could negatively affect food and nutrient intake and thereby contribute to cachexia progression.