不同的FOXA1突变驱动前列腺瘤形成和耐治疗的细胞可塑性
Sanjana Eyunni1,2,3, Rahul Mannan1,2, Yuping Zhang1,2
1Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
概括
不同的FOXA1突变导致前列腺癌的进展. 一类突变促进了雄激素依赖的瘤,而二类突变通过重新编程细胞使治疗具有抵抗力.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 在前列腺癌中,叉头盒A1 (FOXA1) 经常发生变化,但其体内致癌作用尚不清楚.
- 了解FOXA1的功能对于开发向性前列腺癌治疗至关重要.
研究的目的:
- 阐明前列腺癌中不同FOXA1突变的体内致癌机制.
- 调查不同FOXA1变化如何促进瘤的开始和进展.
主要方法:
- 开发特定FOXA1突变的小鼠模拟模型.
- 前列腺组织和器官的组织病理和多核分析.
- 研究包括mTOR,AR,KLF5和AP-1在内的信号通路.
主要成果:
- 通过mTORC1/ 2和AR联合激活,驱动与p53无活化的1类FOXA1突变.
- 类2FOXA1突变诱导光细胞重编程到类似于原始细胞的状态,激活KLF5和AP-1.
- 2类突变促进细胞存活和增殖,即使在较低的雄激素条件下,表明治疗耐药性.
结论:
- 在前列腺癌中,FOXA1充当多面性瘤基因.
- 不同的FOXA1突变类使用不同的策略来驱动瘤发生和耐治疗进展.
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