Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity
Sanjana Eyunni, Rahul Mannan, Yuping Zhang, Eleanor Young, Qiuyang Zhang, Jie Luo, Matthew Pang, Somnath Mahapatra, Jean C. Tien, James 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 Cieślik, Arul M. Chinnaiyan, Abhijit Parolia
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 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.