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激活转录因子3的阿基纳特异性损失限制了KRAS^G12D介导的转录变化和PanIN进展

Mickenzie B Martin^1,2, Fatemeh Mousavi^1,2, Gavin Goebel^1,2

¹Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Cell death discovery

|November 6, 2025

概括

激活转录因子3 (ATF3) 的缺失限制了胰腺癌的发病. 在上皮细胞中删除ATF3限制了小鼠的KRAS驱动的胰腺管腺癌 (PDAC) 进展.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学遗传学是一个

背景情况:

胰腺管道腺癌 (PDAC) 是一种致命的癌症,存活率很低.
吸烟和胰腺炎等危险因素诱导了未折叠的蛋白质反应 (UPR).
激活转录因子3 (ATF3),UPR媒介,影响PDAC进展,但其细胞特异性作用尚不清楚.

研究的目的:

为了研究ATF3在PDAC启动中的表皮特异性功能.
为了确定ATF3在PDAC发育过程中是否在上皮细胞内自主作用.

主要方法:

利用基因工程小鼠模型,在胰腺上皮细胞中条件删除ATF3.
将具有全球ATF3删除 (APK) 和阿基纳特异性ATF3删除 (A^acinarPK) 的小鼠与对照组 (Ptf1a^creERT/+KRAS^G12D/+) 进行比较.
在受伤前后使用RNA测序,形态和活力测试分析了胰腺组织和器官.

主要成果:

皮质特异性ATF3删除 (APK) 减少了瘤信号传递和阿基纳分离 (ADM) 的形成.
与对照组相比,APK有机体表现出改变的基因表达,形态和减少的活力.
在体内研究表明,APK和A^acinarPK小鼠的瘤进展和KRAS信号受限.

结论:

在促进PDAC启动方面,ATF3起着细胞自主作用.
缺少ATF3显著限制了KRAS^G12D驱动的PDAC的发展.
针对ATF3可能为PDAC提供治疗策略.

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