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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE336280 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in patients with pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified inflammation and fibrotic remodeling of respiratory accessory muscles as a key feature of human PDAC cachexia. To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodeling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice bearing orthotopic murine pancreatic (KPC) tumors at time points reflective of pre-cachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint). Compared to Sham, KPC mice showed progressive diaphragm myofiber atrophy beginning on D12 (-16 to -24% , D12toendpointvs.Sham,P< 0.05), which preceded reductions in breathing frequency (-55%,P= 0.0074) and diaphragm excursion (-43%,P= 0.0006) observed at endpoint. During the pre-cachexia phase, diaphragms showed significantleukocyte infiltration (+3 fold to +13-fold; D8–endpointvs.Sham,P< 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10–endpointvs.Sham,P< 0.05), ECM expansion (+1.5 to +1.8-fold; D14–endpointvs.Sham),P<0.05) and collagen accumulation (+3.8-fold; Endpointvs.Sham,P= 0.0013). These processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-B1, Angiotensin, and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodeling associated with denervation. In summary, our data support leukocyte infiltration and fibroadipogenic progenitor expansion as early events that precede wasting and fibrotic remodeling of respiratory muscles in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.

Project description:Cachexia is a highly debilitating multifactorial syndrome affecting more than 50% of patients with advanced cancer. RAGE (receptor for advanced glycation end-products) signaling in mice sustains hallmarks of cancer cachexia (CC), including inflammation, the release of tumor-derived CC factors, and skeletal muscle catabolism. Indeed, mice lacking RAGE (Ager−/− mice) showed delayed loss of muscle mass and strength and dramatically increased survival. Here, we investigated the specific contribution to CC of RAGE expressed at tumor and muscle level by using: i) WT and Ager−/− mice subcutaneously injected with LLC (Lewis lung carcinoma) cell clones stably transfected with full-length (fl) RAGE, RAGEΔcyto (a non-transducing form of RAGE) or empty vector; and, ii) a newly generated tamoxifen-inducible conditional AgermKO mouse model, in which the RAGE gene is selectively deleted in skeletal muscles, injected with LLC cells. We found that: i) modulation of RAGE expression in LLC clones did not alter their cachectic potential; ii) Ager−/− mice did not activate muscle catabolism irrespective of the injected LLC clone, suggesting that RAGE overexpression in the tumor is not sufficient per se to induce muscle atrophy; and, iii) LLC-injected AgermKO mice showed increased survival, maintenance of muscle performance, resistance to the loss of body, muscle mass and performance, and reduced circulating CC factors compared with LLC-bearing control (Agerflox) mice. An increase in hybrid myofibers expressing both slow and fast MyHC isoforms characterized muscles of LLC-AgermKO . Different and unexpected proteomic signatures were found in muscles of tumor-bearing mice in dependence on RAGE expression and thirty-five proteins emerged as modulated in common in LLC/AgermKO and LLC/Ager–/– vs LLC/Agerflox mice suggesting novel mechanisms involved in the resistance against CC. Thus, RAGE engagement at myofiber rather than tumor level is a determinant in sustaining CC. Nevertheless, total ablation of the receptor maximally protects against cancer-induced muscle wasting, indicating that systemic targeting of RAGE might represent a promising strategy to counteract the cachexia syndrome in cancer patients.

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

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