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

Junji Kurashige,Mitsuru Sasako,Seigo Kitano,Satoru Miyano,Ryutaro Uchi,Takanori Hasegawa,Shin Sasaki,Atsushi Niida,Hiroki Sasaki,Yusuke Takahashi,Hidetoshi Eguchi,Koshi Mimori,Kosuke Mima,Takeo Fukagawa,Masaki Mori,Genta Sawada,Hideo Baba,Niantao Deng,Kazuyoshi Yanagihara,Patrick Tan,Keizō Sugimachi ,Masafumi Inomata

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.

Highlights

Frequent cause of death in patients with advanced GC3
By a combined analysis of in vitro and clinical datasets, we identified a GDES comprising genes whose expression levels are associated with gastric peritoneal dissemination
Among the genes in the GDES, our experiments showed that discoidin domain receptor 2 (DDR2) was responsible for peritoneal dissemination

Summary

Introduction

Frequent cause of death in patients with advanced GC3. the mechanisms underlying peritoneal dissemination have not yet been specified, and advanced GC remains an incurable condition. We established 4 cell lines with a high capability for peritoneal dissemination using 12 cycles of orthotropic transplantation directly into the gastric walls of nude mice and harvesting cells from ascites after peritoneal dissemination[4,5]. The phenotypes of these in vivo-selected GC cell lines resemble those in GC patients with peritoneal dissemination; we were motivated to study the gene signatures of these cells to clarify the molecular mechanism of dissemination. To clarify the mechanisms of peritoneal dissemination in GC, we performed combined expression analyses of metastatic cell lines established from a peritoneal dissemination-xenograft mouse model and a clinical dataset of 200 GC patients

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Conclusion