title: Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFβ-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Chen
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA [2] Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Niki A
authors.initials: NA
authors.lastname: Ottenhof
authors.affiliation: Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Roeland F
authors.initials: RF
authors.lastname: de Wilde
authors.affiliation: Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, WA, USA.
authors.forename: Damon H
authors.initials: DH
authors.lastname: May
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Crispin
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lai
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Lay
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Waghray
authors.affiliation: Department of Pathology, Soochow University School of Medicine, Suzhou, China.
authors.forename: Shouli
authors.initials: S
authors.lastname: Wang
authors.affiliation: Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, WA, USA.
authors.forename: Martin W
authors.initials: MW
authors.lastname: McIntosh
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brentnall
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000601:surgery; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000601:surgery; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000601:surgery; D040901:Proteomics; D016019:Survival Analysis
chemical_list: D009363:Neoplasm Proteins