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

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.

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。