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Cell. 2018 Aug 9;174(4):856-869.e17. doi: 10.1016/j.cell.2018.07.027.

Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis.

Author information

1
Department of Gastroenterology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
2
Department of Gastroenterology, Keio University School of Medicine, Tokyo, 160-8582, Japan; Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga 520-0106, Japan.
3
Department of Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
4
Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, 1030, Austria.
5
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, 104-0045, Japan.
6
Department of Gastroenterology, Keio University School of Medicine, Tokyo, 160-8582, Japan. Electronic address: t.sato@keio.jp.

Abstract

Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers.

KEYWORDS:

CRISPR-Cas9; Gastric cancers; Organoids; Stem cell niche; Wnt signaling

PMID:
30096312
DOI:
10.1016/j.cell.2018.07.027

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