The impact of diversity on transcriptional heterogeneity of skeletal muscle from pancreatic ductal adenocarcinoma patients

Objective: Cachexia plays a major role in the morbidity and mortality of pancreatic ductal adenocarcinoma (PDAC) patients. The objective of this study is to delineate the molecular pathways of muscle that contribute to cancer cachexia from surgically resected PDAC patients. Methods: At surgical resection for PDAC, rectus abdominus muscle was sharply divided and shock frozen immediately for RNA-seq. Total RNA was extracted from the frozen tissue using standard protocols, and RNA integrity was confirmed prior to library preparation. The resulting high-quality RNA was then used for RNA sequencing (RNA-seq) analysis to find distinct variants in addition to a core transcriptional signature of roughly 13,007 frequently expressed transcripts, differential transcript expression was evaluated. KEGG pathways and MSigDB collections (Hallmark, Curated, GO signatures) were used in Gene Set Enrichment Analysis (GSEA), which uses both fold change and ranking of differentially expressed genes (DEGs) to find enriched biological pathways. Results: Significant transcriptome variations in muscle tissue were found to be associated with patient race and survival. MSigDB gene sets comparing Black and White ) patients revealed that the AA cohort had higher activation of pathways linked to inflammation, cardiomyopathy, and muscle atrophy/proteostasis. Three overlapping genes were found by cross-referencing these pathways with significant DEGs: CYP4B1, DDIT4 (upregulated in AA, significantly related with muscular atrophy/cachexia), and GINS1 (downregulated in AA, associated with proliferation). Additionally, eight genes including the physiologically significant genes ADAM28, SENCR, and MEG8 (related with muscle differentiation and tumor progression) were found to be substantially associated with overall survival. Conclusion: RNA-seq and GSEA of muscle tissue provide critical insights into the systemic molecular alterations associated with PDAC. The identified pathways and genes, particularly those demonstrating racial and survival-associated heterogeneity (e.g., DDIT4, GINS1), represent potential biomarkers and therapeutic targets for addressing muscle dysfunction and cachexia in PDAC.