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, Yasutaka Sukawa, Hiroki Ishida, Shinya Sugimoto, Hirofumi Kawakubo, Jihoon Kim, Yuko Kitagawa, Shigeki SekineBon Kyoung Koo, Takanori Kanai, Toshiro Sato

Research output: Contribution to journalArticle

35 Citations (Scopus)

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. Generation and analysis of a human gastric cancer organoid bank reveal insights into molecular features underlying diverse histopathological subtypes and tumor independence from Wnt signals.

Original languageEnglish
Pages (from-to)856-869.e17
JournalCell
Volume174
Issue number4
DOIs
Publication statusPublished - 2018 Aug 9

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Nanki, K., Toshimitsu, K., Takano, A., Fujii, M., Shimokawa, M., Ohta, Y., Matano, M., Seino, T., Nishikori, S., Ishikawa, K., Kawasaki, K., Togasaki, K., Takahashi, S., Sukawa, Y., Ishida, H., Sugimoto, S., Kawakubo, H., Kim, J., Kitagawa, Y., ... Sato, T. (2018). Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis. Cell, 174(4), 856-869.e17. https://doi.org/10.1016/j.cell.2018.07.027