来自APC突变细胞的NOTUM偏向于克隆竞争以启动癌症
Dustin J Flanagan1, Nalle Pentinmikko2,3, Kalle Luopajärvi2,3
1Cancer Research UK Beatson Institute, Glasgow, UK.
Nature
|June 3, 2021
概括
结直肠癌中的APC突变细胞使用NOTUM抑制野生类型细胞,从而获得竞争优势. 抑制NOTUM可以防止瘤生长,提供潜在的预防策略.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 在结直肠癌 (CRC) 中,瘤抑制剂结直肠多样性 (APC) 经常发生突变.
- 肠干细胞中的APC损失通过WNT信号促进腺瘤的形成,但矛盾的是,减少WNT连接体分泌有助于突变细胞的殖民 (固定).
研究的目的:
- 研究Apc突变细胞在肠道密室中获得克隆优势和固定的机制.
- 识别使 Apc 突变细胞在野生类型对应物上扩张的分子媒介.
主要方法:
- 对APC突变细胞与野生类型肠道细胞的转录组分析.
- 在体外有机体培养和条件介质实验.
- 在体内研究涉及遗传或药理抑制NOTUM.
主要成果:
- Apc突变细胞对WNT抗体转录物,特别是NOTUM进行了丰富.
- 通过NOTUM从Apc突变细胞中制造的条件介质抑制了野生类型的有机体生长.
- 分泌NOTUM的Apc-突变克隆抑制了野生类型细胞的增殖,促进了分化,从而在利基占用方面超越了它们.
结论:
- 在结直肠癌中,NOTUM是早期固定 Apc 突变细胞的关键媒介.
- 向NOTUM可以恢复野生细胞的竞争力,并抑制腺瘤的形成.
- 对于高风险的个体来说,NOTUM抑制是一种潜在的预防策略.
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