Purinergic and metabolic features are assocIated with cachexia severity in patient-derived pancreatic cancer xenografts

Abstract Background Cancer cachexia is a multifactorial syndrome characterized by involuntary skeletal muscle loss, functional impairment, metabolic dysregulation, and systemic inflammation, and it is highly prevalent in pancreatic ductal adenocarcinoma (PDAC). Experimental models based on tumor cell lines incompletely reflect the clinical heterogeneity of cachexia. In this study, we compared the host phenotypes induced by two PDAC patient-derived xenografts and examined whether selected tumor-associated molecular features were associated with the observed degree of wasting. Methods BALB/c nude mice were subcutaneously engrafted with PDAC fragments from two donors (PDX08 and PDX12). Longitudinal analyses included body weight, estimated tumor-free body weight, food intake, locomotor activity, and muscle endurance. At endpoint, skeletal and cardiac muscle, adipose tissues, visceral organs, and tumors were assessed. A targeted, hypothesis-driven exploratory panel included muscle atrophy F-box (MAFbx/Atrogin-1), muscle-specific RING finger 1 (MuRF1), uncoupling protein 1 (Ucp1), interleukin 6 (IL6), interleukin 1 beta (IL1B), tumor necrosis factor (TNF), purinergic receptor P2Y2 (P2RY2), argininosuccinate synthase 1 (ASS1), and hypoxia-inducible factor 1 alpha (HIF1A). Association between tumor-marker expression and overall survival were examined in The Cancer Genome Atlas. Results PDX08 mice failed to gain weight, reaching a final body weight approximately 17% lower than controls and 25% lower than PDX12 mice. Estimated tumor-free body weight change was − 3.15 ± 2.16 g in PDX08, compared with gains of 5.05 ± 1.15 g in controls and 4.61 ± 0.96 g in PDX12. PDX08 mice showed marked gastrocnemius loss (38%) and visceral white adipose tissue depletion (93%). PDX12 mice showed milder gastrocnemius loss (15%), preserved visceral white adipose tissue, and brown adipose tissue loss (25%). Both models showed functional impairment and increased muscle catabolic and adipose Ucp1 transcripts without reduced food intake. Relative to PDX12, PDX08 tumors had higher IL1B and P2RY2 and lower ASS1 mRNA levels. High P2RY2 expression was associated with shorter overall survival in TCGA-PAAD (nominal log-rank p = 0.03). Conclusions These two PDX-based models produced contrasting wasting phenotypes under standardized host conditions. Differences in tumor P2RY2 and ASS1 expression provide a starting point for investigating how purinergic signaling and arginine metabolism relate to systemic wasting. These findings support further mechanistic evaluation across additional PDX lines.