文章：

NOTCH与AKT信号通路相互作用驱动乳腺肿瘤异质性

NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity

原文发布日期：29 August 2023

DOI: 10.3390/cancers15174324

类型: Article

开放获取: 是

英文摘要：

A better understanding of the mechanisms generating tumour heterogeneity will allow better targeting of current therapies, identify potential resistance mechanisms and highlight new approaches for therapy. We have previously shown that in genetically modified mouse models carrying conditional oncogenic alleles, mammary tumour histotype varies depending on the combination of alleles, the cell type to which they are targeted and, in some cases, reproductive history. This suggests that tumour heterogeneity is not a purely stochastic process; rather, differential activation of signalling pathways leads to reproducible differences in tumour histotype. We propose the NOTCH signalling pathway as one such pathway. Here, we have crossed conditional knockoutNotch1orNotch2alleles into an established mouse mammary tumour model.Notch1/2deletion had no effect on tumour-specific survival; however, loss ofNotchalleles resulted in a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs). ASQCs and adenomyoepitheliomas (AMEs) also demonstrated a significant increase in AKT signalling independent ofNotchstatus. Therefore, the NOTCH pathway is a suppressor of the ASQC phenotype, while increased PI3K/AKT signalling is associated with ASQC and AME tumours. We propose a model in which PI3K/AKT and NOTCH signalling act interact to determine mouse mammary tumour histotype.

摘要翻译： 

深入理解肿瘤异质性产生的机制，将有助于更精准地靶向现有疗法、识别潜在的耐药机制并揭示新的治疗途径。我们先前的研究表明，在携带条件性致癌等位基因的基因修饰小鼠模型中，乳腺肿瘤的组织学类型会因等位基因组合、靶向细胞类型以及在某些情况下的生殖史而异。这表明肿瘤异质性并非纯粹的随机过程；相反，信号通路的差异性激活会导致肿瘤组织学类型出现可重复的差异。我们提出NOTCH信号通路即为其中一条关键通路。本研究将条件性敲除的Notch1或Notch2等位基因导入已建立的小鼠乳腺肿瘤模型。Notch1/2缺失对肿瘤特异性生存期无显著影响；然而，Notch等位基因的缺失导致化生性腺鳞癌（ASQCs）呈剂量依赖性增加。无论NOTCH状态如何，ASQCs和腺肌上皮瘤（AMEs）均显示AKT信号显著增强。因此，NOTCH通路是ASQC表型的抑制因子，而PI3K/AKT信号增强与ASQC和AME肿瘤相关。我们提出一个模型，其中PI3K/AKT与NOTCH信号通过相互作用共同决定小鼠乳腺肿瘤的组织学类型。

原文链接：

NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity