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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Antigens, CD / genetics
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cadherins / genetics
  • Carcinogenesis
  • Cell Proliferation
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation
  • Organoids / metabolism
  • Organoids / pathology*
  • Stomach / pathology*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Thrombospondins / genetics
  • Thrombospondins / metabolism*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Xenograft Model Antitumor Assays


  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • Cadherins
  • RSPO1 protein, human
  • TP53 protein, human
  • Thrombospondins
  • Tumor Suppressor Protein p53
  • Wnt Proteins