在体内CRISPR屏幕中发现MEN1在调节瘤微环境相互作用中的双重功能
Peiran Su1,2, Yin Liu3, Tianyi Chen2
1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Nature genetics
|September 3, 2024
概括
这项研究确定MEN1是影响瘤生长的关键基因,通过影响瘤微环境. 通过调节免疫细胞透,准MEN1显示出对固体癌症疗法的希望.
科学领域:
- 在瘤学瘤学.
- 基因组学就是基因组学.
- 免疫学 免疫学 免疫学
背景情况:
- 二维 (2D) 细胞培养模型在识别影响瘤微环境的治疗点方面存在局限性.
- 了解影响瘤生长的基因,对于开发有效的癌症疗法至关重要.
研究的目的:
- 通过比较2D培养中的功能性基因组查与体内异种移植中的功能性基因组查来确定影响瘤微环境的治疗标.
- 阐明 MEN1 影响瘤生长和免疫细胞透的机制.
主要方法:
- 在二维培养和异种移植中比较CRISPR-Cas9屏幕.
- 在各种固体癌症类型中,MEN1是致命的.
- 在免疫缺陷和免疫能力强小鼠的体内瘤生长测定.
- 染色体免疫沉测序 (ChIP-seq) 用于评估MLL1占用率和H3K4me3.
- 药理上抑制了脑膜-MLL相互作用.
主要成果:
- 鉴于MEN1在体外和体内产生不同效应,被确定为最受欢迎的药物.
- MEN1淘汰赛没有影响体外增殖,但在小鼠中调节了瘤生长.
- MEN1淘汰赛改变了MLL1染色体占用率,增加了重复元素中的H3K4me3,并调节了dsRNA表达.
- MEN1敲击促进了中性粒细胞和CD8+T细胞的透.
- 梅因-MLL抑制以 CD8+ T 细胞依赖的方式降低了瘤生长.
结论:
- MEN1表现出由瘤微环境影响的上下文依赖的瘤和瘤抑制功能.
- 向MEN1通过调节免疫反应,为固体癌症提供了潜在的治疗策略.
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