Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination

Sci Rep. 2016 Mar 3;6:22371. doi: 10.1038/srep22371.

Abstract

Peritoneal dissemination is the most frequent, incurable metastasis occurring in patients with advanced gastric cancer (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to provide novel insights into the molecular mechanisms that drive the peritoneal dissemination of GC. We performed combined expression analysis with in vivo-selected metastatic cell lines and samples from 200 GC patients to identify driver genes of peritoneal dissemination. The driver-gene functions associated with GC dissemination were examined using a mouse xenograft model. We identified a peritoneal dissemination-associated expression signature, whose profile correlated with those of genes related to development, focal adhesion, and the extracellular matrix. Among the genes comprising the expression signature, we identified that discoidin-domain receptor 2 (DDR2) as a potential regulator of peritoneal dissemination. The DDR2 was upregulated by the loss of DNA methylation and that DDR2 knockdown reduced peritoneal metastasis in a xenograft model. Dasatinib, an inhibitor of the DDR2 signaling pathway, effectively suppressed peritoneal dissemination. DDR2 was identified as a driver gene for GC dissemination from the combined expression signature and can potentially serve as a novel therapeutic target for inhibiting GC peritoneal dissemination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dasatinib / pharmacology
  • Discoidin Domain Receptor 2 / genetics
  • Discoidin Domain Receptor 2 / metabolism*
  • Female
  • Gene Expression Profiling
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Peritoneal Neoplasms / enzymology*
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / secondary
  • Signal Transduction*
  • Stomach Neoplasms / enzymology*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / pathology

Substances

  • Neoplasm Proteins
  • DDR2 protein, human
  • Discoidin Domain Receptor 2
  • Dasatinib