title: Integration of metabolomics and transcriptomics revealed a fatty acid network exerting growth inhibitory effects in human pancreatic cancer.
abstract: OBJECTIVE
  To identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma (PDAC), we investigated gene-metabolite networks with integration of metabolomics and transcriptomics.
  
  
  METHODS
  We conducted global metabolite profiling analysis on two independent cohorts of resected PDAC cases to identify critical metabolites alteration that may contribute to the progression of pancreatic cancer. We then searched for gene surrogates that were significantly correlated with the key metabolites, by integrating metabolite and gene expression profiles.
  
  
  RESULTS
  Fifty-five metabolites were consistently altered in tumors as compared with adjacent nontumor tissues in a test cohort (N = 33) and an independent validation cohort (N = 31). Weighted network analysis revealed a unique set of free fatty acids (FFA) that were highly coregulated and decreased in PDAC. Pathway analysis of 157 differentially expressed gene surrogates revealed a significantly altered lipid metabolism network, including 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 FFAs. More importantly, a lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. We further showed that two saturated FFAs, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells.
  
  
  CONCLUSIONS
  Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of FFAs, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention.
authors.affiliation: Authors' Affiliations: Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, Center for Cancer Research, Genetics Branch, National Cancer Institute, NIH, Bethesda; Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Division of Surgical Oncology, The Department of Surgery and the Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; and Department of General and Visceral Surgery, University Medicine, Göttingen, Germany.
authors.forename: Geng
authors.initials: G
authors.lastname: Zhang
authors.forename: Peijun
authors.initials: P
authors.lastname: He
authors.forename: Hanson
authors.initials: H
authors.lastname: Tan
authors.forename: Anuradha
authors.initials: A
authors.lastname: Budhu
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Harris G
authors.initials: HG
authors.lastname: Yfantis
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005227:Fatty Acids / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D050356:Lipid Metabolism; D055432:Metabolomics; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D005227:Fatty Acids; D012333:RNA, Messenger
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