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

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Article number22371
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Mar 3 2016

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Stomach Neoplasms
Heterografts
Genes
Neoplasm Metastasis
Focal Adhesions
DNA Methylation
Transcriptome
Extracellular Matrix
Discoidin Domain Receptor 2
Cell Line

All Science Journal Classification (ASJC) codes

  • General

Cite this

Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination. / Kurashige, Junji; Hasegawa, Takanori; Niida, Atsushi; Sugimachi, Keishi; Deng, Niantao; Mima, Kosuke; Uchi, Ryutaro; Sawada, Genta; Takahashi, Yusuke; Eguchi, Hidetoshi; Inomata, Masashi; Kitano, Seigo; Fukagawa, Takeo; Sasako, Mitsuru; Sasaki, Hiroki; Sasaki, Shin; Mori, Masaki; Yanagihara, Kazuyoshi; Baba, Hideo; Miyano, Satoru; Tan, Patrick; Mimori, Koshi.

In: Scientific reports, Vol. 6, 22371, 03.03.2016.

Research output: Contribution to journalArticle

Kurashige, J, Hasegawa, T, Niida, A, Sugimachi, K, Deng, N, Mima, K, Uchi, R, Sawada, G, Takahashi, Y, Eguchi, H, Inomata, M, Kitano, S, Fukagawa, T, Sasako, M, Sasaki, H, Sasaki, S, Mori, M, Yanagihara, K, Baba, H, Miyano, S, Tan, P & Mimori, K 2016, 'Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination', Scientific reports, vol. 6, 22371. https://doi.org/10.1038/srep22371
Kurashige, Junji ; Hasegawa, Takanori ; Niida, Atsushi ; Sugimachi, Keishi ; Deng, Niantao ; Mima, Kosuke ; Uchi, Ryutaro ; Sawada, Genta ; Takahashi, Yusuke ; Eguchi, Hidetoshi ; Inomata, Masashi ; Kitano, Seigo ; Fukagawa, Takeo ; Sasako, Mitsuru ; Sasaki, Hiroki ; Sasaki, Shin ; Mori, Masaki ; Yanagihara, Kazuyoshi ; Baba, Hideo ; Miyano, Satoru ; Tan, Patrick ; Mimori, Koshi. / Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination. In: Scientific reports. 2016 ; Vol. 6.
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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.",
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