Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity
Menée à partir de modèles murins, d'organoïdes ainsi que d'analyses histopathologiques et multiomiques de tissus prostatiques, cette étude met en évidence, au niveau du gène du facteur de transcription FOXA1, des classes distinctes de mutations qui favorisent soit la tumorigenèse (mutations de classe 1), soit la plasticité cellulaire et la résistance thérapeutique (mutations de classe 2)
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.
Science , résumé, 2025