NOTCH和AKT信号交互驱动乳腺瘤异质性
Liliana Ordonez1, Giusy Tornillo1, Howard Kendrick1
1The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
Cancers
|September 9, 2023
概括
该NOTCH途径抑制了小鼠乳腺瘤中的代塑性腺性瘤 (ASQCs). 失去NOTCH1/2等位基因会增加ASQC,这表明PI3K/AKT和NOTCH信号相互作用会影响瘤类型.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 瘤异质性影响治疗策略和抵抗机制.
- 在小鼠模型中,乳腺瘤基因型取决于致癌等位基因,细胞类型和生殖史,这表明非静态起源.
- 信号通路在确定瘤组织型的可复制差异方面发挥着关键作用.
研究的目的:
- 研究NOTCH信号通路在调节小鼠乳腺瘤异质性的作用.
- 确定NOTCH1和NOTCH2删除对乳腺瘤发育和组织型的影响.
- 探索NOTCH信号传递,PI3K/AKT信号传递,以及转移性状腺癌 (ASQCs) 和腺肌上皮瘤 (AME) 的发展之间的关系.
主要方法:
- 利用了基因改造的小鼠模型,对Notch1或Notch2.2具有条件淘汰等位基因.
- 将这些条件淘汰等位基交叉到已建立的小鼠乳腺瘤模型中.
- 分析了瘤组型,瘤特异性存活率和在NOTCH等位基因存在或不存在时的AKT信号激活.
主要成果:
- 删除Notch1/2等位基因并没有影响瘤特异性生存率.
- 对NOTCH等位基因的丧失导致了对甲基塑性腺素状瘤 (ASQCs) 的剂量依赖性增加.
- 无论NOTCH状态如何,ASQC和腺肌上皮瘤 (AME) 都显示出AKT信号的增加.
结论:
- 在小鼠乳腺瘤中,NOTCH通路作为ASQC表型的抑制剂.
- 增加PI3K/AKT信号显著与ASQC和AME瘤发育有关.
- 提出了一个模型,其中PI3K/AKT和NOTCH信号通路相互作用以确定小鼠乳腺瘤组织型.
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