Neutral selection and clonal expansion during the development of colon cancer metastasis.

IF 2.1 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xuelian Lei, Daisuke Yamamoto, Hirotaka Kitamura, Kenji Kita, Noriyuki Inaki, Kazuhiro Murakami, Mizuho Nakayama, Hiroko Oshima, Masanobu Oshima
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引用次数: 0

Abstract

Intratumour heterogeneity has been shown to play a role in the malignant progression of cancer. The clonal evolution in primary cancer has been well studied, however, that in metastatic tumorigenesis is not fully understood. In this study, we established human colon cancer-derived organoids and investigated clonal dynamics during liver metastasis development by tracking barcode-labelled subclones. Long-term subclone co-cultures showed clonal drift, with a single subclone becoming dominant in the cell population. Interestingly, the selected subclones were not always the same, suggesting that clonal selection was not based on cell intrinsic properties. Furthermore, liver tumours developed by co-transplantation of organoid subclones into the immunodeficient mouse spleen showed a progressive drastic reduction in clonal diversity, and only one or two subclones predominated in the majority of large metastatic tumours. Importantly, selections were not limited to particular subclones but appeared to be random. A trend towards a reduction in clonal diversity was also found in liver metastases of multiple colour-labelled organoids of mouse intestinal tumours. Based on these results, we propose a novel mechanism of metastasis development, i.e. a subclone population of the disseminated tumour cells in the liver is selected by neutral selection during colonization and constitutes large metastatic tumours.

结肠癌转移发展过程中的中性选择和克隆扩增。
肿瘤内的异质性已被证明在癌症的恶性发展中发挥作用。尽管对原发性癌症中的克隆演化已有深入研究,但对转移性肿瘤发生过程中的克隆演化还不完全了解。在这项研究中,我们建立了人结肠癌器官组织,并通过追踪条形码标记的亚克隆研究了肝转移发展过程中的克隆动态。长期的亚克隆共培养显示出克隆漂移,单个亚克隆在细胞群中占据主导地位。有趣的是,被选择的亚克隆并不总是相同的,这表明克隆选择并非基于细胞的内在特性。此外,将类器官亚克隆共同移植到免疫缺陷小鼠脾脏而形成的肝脏肿瘤显示,克隆多样性逐渐急剧下降,在大多数大的转移性肿瘤中,只有一个或两个亚克隆占主导地位。重要的是,选择并不局限于特定的亚克隆,而似乎是随机的。在小鼠肠道肿瘤的多个彩色标记器官组织的肝转移瘤中也发现了克隆多样性减少的趋势。基于这些结果,我们提出了一种新的转移发展机制,即肝脏中扩散的肿瘤细胞的亚克隆群体在定殖过程中被中性选择,并构成大型转移性肿瘤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of biochemistry
Journal of biochemistry 生物-生化与分子生物学
CiteScore
4.80
自引率
3.70%
发文量
101
审稿时长
4-8 weeks
期刊介绍: The Journal of Biochemistry founded in 1922 publishes the results of original research in the fields of Biochemistry, Molecular Biology, Cell, and Biotechnology written in English in the form of Regular Papers or Rapid Communications. A Rapid Communication is not a preliminary note, but it is, though brief, a complete and final publication. The materials described in Rapid Communications should not be included in a later paper. The Journal also publishes short reviews (JB Review) and papers solicited by the Editorial Board.
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