Down‐regulation of metabolic pathways could offset the poor prognosis conferred by co‐existent diabetes mellitus in pancreatic (head) adenocarcinoma

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision‐oncology for which we systematically analysed publicly‐available PDAC transcriptome data. Methods PDAC TCGA RNASeq data were used. Analyses were restricted to only ‘high purity’ and ‘head’ as anatomical site. Patients were characterised by: (1) Gene expression classification, and (2) Weighted gene correlation network analysis (WGCNA) to identify co‐expression patterns of genes. Newly identified gene signature subclasses of pancreatic head PDAC were associated with clinical and functional characteristics of patients. Results Consensus clustering identified two patient subclasses within PDAC involving pancreatic head. WGCNA identified 11 distinct networks of gene expression patterns across two sub‐classes. Class 1 patients demonstrated a significant upregulation of Module 5 and Module 6 gene expression compared to Class 2. Class 1 predominantly expressed the acinar, ductal and islet cell gene signatures. There were significantly less patients with DM in Class 1 subclass compared to Class 2 (p < 0.037). Patients with DM had significant downregulation of pathways involved in cellular metabolism, hormone secretion and paucity of islet cell markers with no reduced survival compared with non‐diabetics. Conclusions A significant proportion of patients with PDAC of pancreatic head and DM exhibit downregulation of pathways involved in cellular metabolism, hormone secretion and signalling accompanied by a paucity of islet expression. Investigating the relationship between DM and gene expression profiles in patients with PDAC presents opportunities to improve overall survival in diabetics with PDAC.

Identification of Carcinogenesis and Tumor Progression Processes in Pancreatic Ductal Adenocarcinoma Using High-Throughput Proteomics

“…In addition, in a previous proteomics study in hepatic PDAC metastases, a group related to metabolism was defined, characterized by the expression of ethanol oxidation, mitochondrial fatty-acid beta oxidation, and retinoic acid signaling pathways [9]. Moreover, the downregulation of certain metabolic pathways in patients with PDAC and diabetes mellitus has been suggested to be associated with the poor prognosis of these patients [35]. Metabolism and pancreatic secretion nodes had differential activity between T2 normal tissue, PanIN, and tumors and between tumors and lymph nodes.…”

Robust Validation and Comprehensive Analysis of a Novel Signature Derived from Crucial Metabolic Pathways of Pancreatic Ductal Adenocarcinoma

“…PDAC accounts for the majority of pancreatic cancer cases (>85% of all cases), while pancreatic endocrine tumors represent <5% [ 12 , 13 , 14 ]. Pancreatic cancer cells are tumor cells that have extensively reprogrammed metabolic characteristics influenced by interactions with normal cells, the effects of the tumor microenvironment (TME) and oncogene-mediated cell-autonomous pathways [ 15 , 16 , 17 ]. Glycolysis can be induced by hypoxia and is reported to promote tumor progression and chemoresistance in PDAC [ 18 , 19 , 20 ].…”