Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis
Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis
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DOI：
10.1016/j.cell.2018.07.027
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发表时间：
2018-08-09
期刊：
影响因子：
64.5
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Nanki, Kosaku;Toshimitsu, Kohta;Sato, Toshiro
近期的测序分析揭示了人类胃癌（GCs）中基因组畸变的异质性模式。为了探究个体遗传事件如何转化为癌症表型，我们建立了一个生物库，其中包含携带各种胃癌突变的基因工程胃类器官以及37个患者来源的类器官系，包括罕见的基因组稳定型胃癌。表型生态位独立性。一项基于无偏表型的遗传筛选确定了CDH1/TP53复合突变与R - 脊椎蛋白独立性之间存在显著关联，并且通过基于CRISPR的基因敲除在功能上进行了验证。胃癌类器官的异种移植进一步证实了针对Wnt依赖性胃癌进行Wnt靶向治疗的可行性。我们的研究结果共同表明，多方面的遗传异常使得人类胃癌独立于干细胞生态位，并强调了基因型 - 表型筛选策略在深入了解人类癌症方面的有效性。
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 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 validate 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.