Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis.
Cell
; 174(4): 856-869.e17, 2018 08 09.
Article
em En
| MEDLINE
| ID: mdl-30096312
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.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Estômago
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Neoplasias Gástricas
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Adenocarcinoma
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Organoides
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Trombospondinas
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Proteínas Wnt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Japão