Transcriptome and microRNAome profiling of human skeletal muscle in pancreatic cancer cachexia

Background and Aims: Over 80% of patients with pancreatic cancer experience cachexia, characterized by severe muscle and fat loss. While all the mechanistic understanding comes from preclinical models, the translatable nature of these findings to humans remains a critical gap due to the limited knowledge of human cachexia biology. Methods: We generated matched gene and microRNA profiles from rectus abdominis muscle of 55 pancreatic ductal adenocarcinoma and 18 control subjects. Differentially expressed genes and microRNAs were identified at 1.5-fold change and p<0.05. Results: Gene expression results revealed a striking sex-specific difference at the expression and pathway levels. In both sexes, co-expression gene network analysis identified more significant modules and hub genes at 1-month of weight loss than the traditionally used six months, suggesting that gene alterations may be more dynamic in the early stages of the disease progression. When comparing hub genes from humans to experimental models of cachexia, genes such as RELA, DDX21, WDR75, PTPN1, and CRIP3 exhibited similar patterns of expression, suggesting their potential role in cachexia. microRNAs also exhibited sex-specific expression. Although several common miRNAs were identified between sexes, their gene targets differed, indicating that microRNAs may regulate gene targets in a sex-specific manner. Conclusions: The dataset can serve as a resource for validating preclinical findings and exploring previously unexplored molecules in cachexia. Future studies will functionally characterize the role of the hub genes and microRNAs in cachexia. This is the first study to identify sex-specific genes and microRNAs from a single cancer type.