Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis
2018
Nanki, Kosaku | Toshimitsu, Kohta | Takano, Ai | Fujii, Masayuki | Shimokawa, Mariko | Ohta, Yuki | Matano, Mami | Seino, Takashi | Nishikori, Shingo | Ishikawa, Keiko | Kawasaki, Kenta | Togasaki, Kazuhiro | Takahashi, Sirirat | Sukawa, Yasutaka | Ishida, Hiroki | Sugimoto, Shinya | Kawakubo, Hirofumi | Kim, Jihoon | Kitagawa, Yuko | Sekine, Shigeki | Koo, Bon-Kyoung | Kanai, Takanori | Sato, Toshiro
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.
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