In a study reported in Clinical Cancer Research, Zhang and colleagues used integrated metabolomics and transcriptomics to investigate gene-metabolic networks and identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma.
A global metabolite profiling analysis was performed on two independent cohorts of resected pancreatic ductal adenocarcinoma cases to identify critical metabolite alterations that may contribute to the progression of cancer. Gene surrogates significantly correlated with the key metabolites were identified by integrating metabolite and gene-expression profiles.
A total of 55 metabolites were consistently altered in tumors compared with adjacent nontumor tissues in a test cohort (n = 33) and an independent validation cohort (n = 31). Weighted network analysis identified a unique set of free fatty acids that were highly coregulated and decreased in pancreatic cancer
Pathway analysis of 157 differentially expressed gene surrogates showed a significantly altered lipid metabolism network, including the key lipolytic enzymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced levels of free fatty acids.
Lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. It was further shown that two saturated free fatty acids, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells.
The investigators concluded, “Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of [free fatty acids], may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention.” ■