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Divergent Routes Toward Wnt and R-spondin Niche Independency During Human Gastric Carcinogenesis

Divergent Routes Toward Wnt and R-spondin Niche Independency During Human Gastric Carcinogenesis

Kosaku Nanki, Kohta Toshimitsu, Ai Takano, Masayuki Fujii, Mariko Shimokawa, Yuki Ohta, Mami Matano, Takashi Seino, Shingo Nishikori, Keiko Ishikawa, Kenta Kawasaki, Kazuhiro Togasaki, Sirirat Takahashi, etc.

Cell. 2018 Aug 9;174(4):856-869.e17.

PMID: 30096312

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42414468	Thrombospondin human			Price

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