Divergent routes toward wnt and R-spondin niche independency during human gastric carcinogenesis

• Kosaku Nanki ^[1] ; Kohta Toshimitsu ^[1] ; Ai Takano ^[1]
  1. [1] Keio University

     Keio University

     Japón

     
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 4, 2018, págs. 856-869
• Idioma: inglés
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• Resumen

  • 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.