Abstract 2866: Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma
Authors: Chen Ru , Pan Sheng , Maitra Anirban , Simeone Diane , Dawson David , Brentnall Teresa 
Published: May 2015

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is dismal. Very rarely, patients will survive for more than10-years after pancreatic surgery. A few clinicopathological characteristics have been demonstrated to have significant effect on long-term survival. However, the molecular characteristics of the pancreatic adenocarcinomas from these very long-term survivors (VLTS) remain to be uncovered. Our study investigated the tissue proteome of pancreatic tumor and sought to characterize protein signatures associated with pancreatic cancer survival. A comparative label-free proteomics approach was applied to investigate the formalin-fixed paraffin-embedded tumor tissues from five VLTS patients (survival &gt;10 years) and five short-term survival patients (STS, survival &lt;14 months) to identify differentially expressed proteins associated with VLTS and STS. The major functional clusters of the STS associated proteins included cytoskeleton, ribonucleoprotein complex/ protein biosynthesis/RNA processing, and generation of precursor metabolites and energy. In contract, the major functional clusters of the VLTS associated proteins included copines, mitochondrion, and generation of precursor metabolites and energy. Pathway analysis identified MYC, IGF1R and p53 as the top three upstream regulators for the STS associated proteins, and VEGFA, APOE, and TGFβ-1as the top three upstream regulators for the VLTS associated proteins. One VLTS-associated protein, prolargin (PRELP), and one STS-associated protein, ribosomal protein S8 (RPS8) were further validated by immunohistochemistry in an independent cohort of patients, constructed in a tissue microarray with 145 cases of PDAC. Increased expression of PRELP was significantly associated with longer survival time (hazard ratio=0.61, 95% confidence interval 0.42-0.91, p=0.015), and increased expression of RPS8 was significantly associated with shorter survival time (hazard ratio=1.79, 95% confidence interval 1.13-2.82, p=0.012). The combination of “RPS8 and PRELP” displayed improved prognostic value over single protein alone. Multivariate Cox analysis confirmed 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 a model with other significant pathologic variables including high histologic grade and positive lymph node involvement. In addition, galectin-1 (LGALS1) - a STS-associate protein, 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, suggesting the important role of galectin-1 in tumor microenvironment. The study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors or potential therapeutic target to improve pancreatic cancer survival.

Citation Format: Ru Chen, Sheng Pan, Anirban Maitra, Diane Simeone, David Dawson, Teresa Brentnall. Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2866. doi:10.1158/1538-7445.AM2014-2866