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.

TAZ has been compensated for consulting work on cancer cachexia, has carried out sponsored research for Leap Therapeutics, and was/is a member of the Scientific Advisory Board of Emmyon, Inc. and PeleOs. However, none of these financial relationships concern the research presented here. The authors declare no further conflicts of interest.

This work was supported in part by grants from the Lustgarten Foundation (TAZ), the National Institutes of Health, including P01 CA236778-01A1 (SC, LGK, TAZ), R01CA257452 (TAZ), T32 CA254888 (BRC), NIH/NCI 1L70CA284463-01 (BRC), the Knight Cancer Institute (NIH grant P30 CA069533), the U.S. Department of Veterans Affairs grant I01CX002046 (TAZ), and the Brenden Colson Center for Pancreatic Care at Oregon Health & Sciences University. Specimen collection and histology were supported by the Biospecimen Collection and Banking Core of the Indiana University Simon Comprehensive Cancer Center (IUSCCC) (NIH grant P30CA082709). Bioinformatics analysis was supported by the Walther Cancer Foundation, the Purdue University Center for Cancer Research (grant P30CA023168) and the IUSCCC. Additional support was provided by the Adams County Cancer Coalition (TAZ).

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