Intra-tumour diversification in colorectal cancer at the single-cell level
Intra-tumour diversification in colorectal cancer at the single-cell level
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DOI：
10.1038/s41586-018-0024-3
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发表时间：
2018-04-26
期刊：
影响因子：
64.8
通讯作者：
Clevers, Hans
中科院分区：
文献类型：
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作者：
Roerink, Sophie F.;Sasaki, Nobuo;Clevers, Hans
每一种癌症都起源于一个细胞。在肿瘤细胞群体的扩增期间，单个细胞获得彼此的遗传和表型差异。在这里，为了研究肿瘤内多样化的性质和程度，我们表征了来自三种结直肠癌以及邻近正常肠隐窝的多个单细胞的类器官。结直肠癌细胞表现出广泛的突变多样性，并携带比正常结直肠细胞多几倍的体细胞突变。大多数突变是在癌症的最终显性克隆扩增期间获得的，并且是由正常结直肠细胞中不存在的突变过程引起的。肿瘤内的DNA甲基化和转录组状态的多样化也发生了;这些变化是细胞自主的，稳定的，并遵循每种癌症的系统发育树。即使是同一肿瘤的密切相关的细胞之间，对抗癌药物的反应也有显着差异。结果表明，与正常结直肠细胞相比，结直肠癌细胞的体细胞突变率大幅增加，并且每种癌症的遗传多样性伴随着个体癌细胞生物学状态的普遍，稳定和遗传差异。
Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.