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

• 成果类型: Article
• 署名作者: Eyunni, Sanjana; Mannan, Rahul; Zhang, Yuping; Young, Eleanor; Zhang, Qiuyang; Luo, Jie; Pang, Matthew; Mahapatra, Somnath; Tien, Jean Ching-Yi; George, James M.; Jaber, Mustapha; Hakkani, Hamzah; Carson, Sandra E.; Todd, Abigail J.; Hosseini, Noshad; Gondal, Mahnoor; Rebernick, Ryan J.; Cao, Xuhong; Su, Fengyun; Wang, Rui; Mehra, Rohit; Li, Jing; Cieslik, Marcin; Chinnaiyan, Arul M.; Parolia, Abhijit
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Howard Hughes Medical Institute; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Naval Medical University; University of Michigan System; University of Michigan
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv2367
• 发表日期: 2025-09-04
• 页码: eadv2367
• 关键词: R/BIOCONDUCTOR PACKAGE; in-vivo; gene; cancer; lineage; recurrent; signatures; landscape; platform; cells

摘要

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 multiomic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction with p53 inactivation, drive androgen-dependent adenocarcinomas through coactivation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. By contrast, Class 2 mutations induce intraluminal 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.