Abstract 133: Skeletal muscle transcriptome profiling of human pancreatic cancer cachexia: single largest study in cachexia

Cancer cachexia is a devastating syndrome characterized by severe depletion of muscle and fat loss. More than 80% of patients with pancreatic ductal adenocarcinoma (PDAC) cancer suffer from cachexia. Virtually all of the mechanistic understanding of cachexia comes from preclinical models; it remains to be seen how much of these molecular findings reflect in human cachexia. To translate the findings, it is important to have a better understanding of the human biology of cachexia. To address this knowledge gap, we performed a single large transcriptome profiling of skeletal muscle biopsies from 18 controls and 55 patients with resectable PDAC. RNA was isolated from rectus abdominus muscle and subjected to total RNA sequencing. Each sample was sequenced to 100 million reads. Differentially expressed (DE) genes were identified using Deseq2 and were subjected to pathway analysis. Further, we performed a sex-stratified analysis to understand if a sex-specific gene pattern exists. To better understand the relationship between clinical variables of cachexia such as 1- and 6-month weight loss, BMI, and skeletal muscle index versus gene expression, we built a sex-specific correlation network using weighted gene co-expression network analysis (WGCNA). As age was significantly different between controls and PDAC, we also performed age-adjusted gene expression analysis. In the overall analysis, 598 genes were DE between controls and PDAC groups. Novel upstream transcription factors including EGR1, EGR2 and EGR3 were identified. Many inflammatory pathways such as IL-6, IL-8, JAK/STAT, and p53 signaling were identified. In sex-specific analyses, 802 genes were DE in males, and 511 in females. Only 86 genes overlapped between males and females, suggesting that gene expression is modulated in a sex-specific fashion. WGCNA identified many significant modules at 1-month weight loss indicating that the gene changes could be dynamic in early stages of weight loss. The key correlated modules in males were enriched for pathways such as Wnt signaling, IL-6 signaling, lipid metabolism and hypoxia signaling. In females, the correlated modules were predominantly associated with DNA repair pathways and epigenetic pathways such as chromatin organization and apoptosis. Overall, this is the single largest cachexia-specific transcriptome profiling performed to date to comprehensively document RNA changes in PDAC cachexia. Our results suggest a strong sex influence at the gene, pathway, and WGCNA analysis levels. The catalog of genes identified from the study can be used be a rich resource for validation of pre-clinical observations and hypothesis generation. Efforts are underway to build an interactive database for public access. Citation Format: Ashok Narasimhan, Xiaoling Zhong, Jun Wan, Sheng Liu, Leonidas G. Koniaris, Teresa A. Zimmers. Skeletal muscle transcriptome profiling of human pancreatic cancer cachexia: single largest study in cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 133.