追踪肠道干细胞的基因驱动改造
Min Kyu Yum1,2, Seungmin Han1,2, Juergen Fink2
1Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
Nature
|June 3, 2021
概括
新的Red2Onco小鼠模型揭示了癌细胞如何重塑它们的微环境. 瘤基因表达的瘤细胞会形成对正常组织有害的,促进癌细胞的生长.
科学领域:
- 癌症学
- 发育生物学
- 遗传学
背景情况:
- 瘤微环境的相互作用导致癌症的进展,转移和复发.
- 研究这些相互作用的脊椎动物模型是有限的.
- 之前对Drosophila的马赛克分析有所进展,但很难将其转化为脊椎动物.
研究的目的:
- 开发一种多色记者小鼠模型,用于在体内追踪突变细胞和野生细胞.
- 研究瘤基因表达细胞如何改变它们周围的微环境.
主要方法:
- 开发Red2Onco系统,一种与瘤基因相关的多色记者小鼠模型.
- 将Red2Onco系统应用于小肠以研究突变细胞和野生细胞之间的相互作用.
- 细胞组织,基因表达 (BMP,WNT) 和细胞结构变化的分析.
主要成果:
- 瘤基因表达突变密码改变了邻近的野生类型密码的组织,导致了加速的克隆漂移.
- 表达瘤性KRAS或PI3K的突变密码分泌BMP连体,抑制局部干细胞活动.
- 致癌的PI3K改变了PDGFRloCD81+细胞结构,改变了WNT信号环境.
结论:
- 通过Red2Onco系统,可以在同一组织内分辨突变细胞和野生细胞.
- 瘤基因驱动的膜重塑会造成一种不利于野生类型组织的维护.
- 这一过程促进了现场转化,有利于瘤克隆的统治地位.
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