Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

Cancer Res. 2016 May 1;76(9):2612-25. doi: 10.1158/0008-5472.CAN-15-1846. Epub 2016 Mar 3.

Abstract

The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma in Situ / genetics
  • Adenocarcinoma in Situ / pathology*
  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / mortality
  • Adenocarcinoma, Mucinous / pathology
  • Adenocarcinoma, Papillary / genetics
  • Adenocarcinoma, Papillary / mortality
  • Adenocarcinoma, Papillary / pathology
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology*
  • Comparative Genomic Hybridization
  • Disease Progression
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Heterografts
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Microscopy, Confocal
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism*
  • Neoplasm Invasiveness
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology*
  • Transcriptome

Substances

  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP4 protein, human
  • Dual-Specificity Phosphatases