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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Integrated one- and two-photon imaging platform reveals clonal expansion as a major driver of mutation load
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Integrated one- and two-photon imaging platform reveals clonal expansion as a major driver of mutation load

机译：集成的单光子和双光子成像平台揭示了克隆扩展是突变负荷的主要驱动力

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摘要

The clonal expansion of mutant cells is hypothesized to be an important first step in cancer formation. To understand the earliest stages of tumorigenesis, a method to identify and analyze clonal expansion is needed. We have previously described transgenic Fluorescent Yellow Direct Repeat (FYDR) mice in which cells that have undergone sequence rearrangements (via homologous recombination events) express a fluorescent protein, enabling fluorescent labeling of phenotypically normal cells. Here, we develop an integrated one- and two-photon imaging platform that spans four orders of magnitude to permit rapid quantification of clonal expansion in the FYDR pancreas in situ. Results show that as mice age there is a significant increase in the number of cells within fluorescent cell clusters, indicating that pancreatic cells can clonally expand with age. Importantly, > 90% of fluorescent cells in aged mice result from clonal expansion, rather than de novo sequence rearrangements at the FYDR locus. The spontaneous frequency of sequence rearrangements at the FYDR locus is on par with that of other classes of mutational events. Therefore, we conclude that clonal expansion is one of the most important mechanisms for increasing the burden of mutant cells in the mouse pancreas.
机译：突变细胞的克隆扩增被认为是癌症形成的重要第一步。为了了解肿瘤发生的最早阶段，需要一种鉴定和分析克隆扩增的方法。我们以前已经描述了转基因荧光黄直接重复（FYDR）小鼠，其中经历了序列重排（通过同源重组事件）的细胞表达荧光蛋白，从而能够对表型正常细胞进行荧光标记。在这里，我们开发了一个集成的单光子和双光子成像平台，该平台跨四个数量级，从而可以快速量化FYDR胰腺原位的克隆扩增。结果表明，随着小鼠年龄的增长，荧光细胞簇中的细胞数量显着增加，这表明胰腺细胞可以随着年龄的增长而克隆。重要的是，老年小鼠中超过90％的荧光细胞是由克隆扩增产生的，而不是FYDR基因座的从头序列重排。 FYDR位点的序列重排自发频率与其他类型的突变事件的频率相同。因此，我们得出结论，克隆扩增是增加小鼠胰腺突变细胞负担的最重要机制之一。

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