Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-06-26 DOI:10.1126/science.adv2367

Sanjana Eyunni, Rahul Mannan, Yuping Zhang, Eleanor Young, Qiuyang Zhang, Jie Luo, Matthew Pang, Somnath Mahapatra, Jean Ching-Yi Tien, James M. George, Mustapha Jaber, Hamzah Hakkani, Sandra E. Carson, Abigail J. Todd, Noshad Hosseini, Mahnoor Gondal, Ryan J. Rebernick, Xuhong Cao, Fengyun Su, Rui Wang, Rohit Mehra, Jing Li, Marcin Cieslik, Arul M. Chinnaiyan, Abhijit Parolia

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引用次数: 0

Abstract

FOXA1 is altered in 10 to 40% of prostate cancers, yet its oncogenic mechanisms remain uncharacterized in vivo. We developed knock-in mouse models representing distinct classes of FOXA1 mutations. Histopathological and multi-omic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction with p53 inactivation, drive androgen-dependent adenocarcinomas through co-activation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. In contrast, Class 2 mutations induce intra-luminal plasticity by reprogramming differentiated luminal cells into a progenitor-like state through activation of KLF5 and AP-1 neo-enhancer circuitries, which enables enhanced survival and proliferation even under castrate androgen levels. Our findings establish FOXA1 as a multifaceted oncogene, with distinct mutational classes divergently evolving to drive prostate tumorigenesis or therapy-resistant progression.

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不同的FOXA1突变驱动前列腺肿瘤发生和抗治疗细胞可塑性

FOXA1在10% - 40%的前列腺癌中发生改变，但其在体内的致癌机制尚不清楚。我们开发了敲入小鼠模型，代表不同种类的FOXA1突变。前列腺组织和类器官的组织病理学和多组学分析显示，1类突变与p53失活一起，通过mTORC1/2和嵌合AR半增强子产生的致癌AR信号的共同激活，驱动雄激素依赖性腺癌。相比之下，2类突变通过激活KLF5和AP-1新增强子回路，将分化的管腔细胞重编程为祖细胞样状态，从而诱导管腔内可塑性，即使在阉割雄激素水平下，也能增强存活和增殖。我们的研究结果表明FOXA1是一个多方面的癌基因，具有不同的突变类别，可以不同地进化以驱动前列腺肿瘤的发生或治疗抵抗性进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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