A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers
A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers
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肿瘤驻留Lgr5+干细胞样库驱动晚期胃癌的建立和进展
DOI：
10.1038/s41556-021-00793-9
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发表时间：
2021-12-02
影响因子：
21.3
通讯作者：
Barker, N.
中科院分区：
文献类型：
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作者：
Fatehullah, A.;Terakado, Y.;Barker, N.
胃癌是全球最常见和最致命的癌症之一。为了深入了解控制这种疾病的途径，我们生成了 Claudin18-IRES-CreERT2 等位基因，以选择性驱动胃上皮内 Wnt、受体酪氨酸激酶和 Trp53 途径的条件性失调。这导致了高度可重复的转移性染色体不稳定型胃癌。与此同时，我们开发了原位癌症类器官移植模型，通过体内消融评估肿瘤驻留 Lgr5(+) 群体作为功能性癌症干细胞的能力。我们发现 Cldn18 肿瘤在疾病形态、异常基因表达、分子标记和远处转移部位方面准确地再现了晚期人类胃癌。重要的是，我们确定肿瘤驻留的Lgr5(+)干细胞对于肿瘤负荷的启动和维持至关重要，并且对于转移的建立是必需的。这些模型对于获得癌症进展的临床相关机制见解以及作为评估治疗靶点的临床前模型将具有无价的价值。Fatehullah 等人。开发转基因和原位小鼠模型来重现晚期人类胃癌，并揭示 Lgr5(+) 干细胞样细胞在促进疾病发生和进展中的机制作用。
Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5(+) populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5(+) stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.Fatehullah et al. develop transgenic and orthotopic mouse models to recapitulate advanced human gastric cancer and uncover a mechanistic role for Lgr5(+) stem-like cells in promoting disease initiation and progression.