Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model

Background Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. Methods...

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Bibliographic Details
Published in:Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2022-09, Vol.25 (5), p.862-878
Main Authors: Yamaguchi, Kyoko, Yoshihiro, Tomoyasu, Ariyama, Hiroshi, Ito, Mamoru, Nakano, Michitaka, Semba, Yuichiro, Nogami, Jumpei, Tsuchihashi, Kenji, Yamauchi, Takuji, Ueno, Shohei, Isobe, Taichi, Shindo, Koji, Moriyama, Taiki, Ohuchida, Kenoki, Nakamura, Masafumi, Nagao, Yoshihiro, Ikeda, Tetsuo, Hashizume, Makoto, Konomi, Hiroyuki, Torisu, Takehiro, Kitazono, Takanari, Kanayama, Tomohiro, Tomita, Hiroyuki, Oda, Yoshinao, Kusaba, Hitoshi, Maeda, Takahiro, Akashi, Koichi, Baba, Eishi
Format: Article
Language:English
Subjects:
Abdominal Surgery
Cancer Research
Cell culture
Cell membranes
Cell survival
CXCL12 protein
CXCR4 protein
E-cadherin
Fibroblasts
Gastric cancer
Gastroenterology
Matrix metalloproteinase
Medicine
Medicine & Public Health
Metalloproteinase
Motility
Oncology
Organoids
Original Article
Stromelysin 1
Surgical Oncology
Therapeutic applications
Therapeutic targets
Transcriptomes
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Summary:Background Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. Methods To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). Results CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. Conclusions E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.
ISSN:1436-3291
1436-3305
DOI:10.1007/s10120-022-01307-8