Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer
Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1<sup>F254E255</sup> is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.
Authors
- Davide Dalfovo (ORCID: https://orcid.org/0000-0002-9760-7655)
- Giulia Beccaceci (ORCID: https://orcid.org/0000-0002-6453-3725)
- Michael M. Shen (ORCID: https://orcid.org/0000-0002-4042-1657)
- Veronica Foletto (ORCID: https://orcid.org/0000-0003-3115-7636)
- Fulvio Chiacchiera (ORCID: https://orcid.org/0000-0003-3830-2090)
- Francesco Cambuli
- Srinivasaraghavan Kannan (ORCID: https://orcid.org/0000-0002-9539-5249)
- Alessandro Romanel (ORCID: https://orcid.org/0000-0003-4855-8620)
- Chandra Shekhar Verma (ORCID: https://orcid.org/0000-0003-0733-9798)
- Federico Cutrupi
- Francesco Gandolfi (ORCID: https://orcid.org/0000-0001-9655-0258)
- Sacha Genovesi (ORCID: https://orcid.org/0000-0002-3568-0048)
- Andrea Lunardi (ORCID: https://orcid.org/0000-0001-6218-2565)
- Marco Lorenzoni (ORCID: https://orcid.org/0000-0002-3040-0633)
- Alessandro Alaimo (ORCID: https://orcid.org/0000-0002-5888-6268)
- Alessandro Vasciaveo (ORCID: https://orcid.org/0000-0003-0205-9869)
- Dario De Felice (ORCID: https://orcid.org/0000-0001-8121-8260)
- Nicole Annesi
- Davide Bressan (ORCID: https://orcid.org/0000-0003-4757-2535)
- Elisa Marmocchi
- Stefano Medaglia
Institutions
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Nanyang Technological University (SG)
- University of Trento (IT)
- Columbia University Irving Medical Center (US)
- Human Technopole (IT)
- Cancer Genetics (United States) (US)
- Bioinformatics Institute (SG)
Publication Details
- Journal
- EMBO Reports
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s44319-024-00335-y
- Citations
- 3
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 1.26
Funders
- U.S. Department of Defense
- Giovanni Armenise-Harvard Foundation
- Worldwide Cancer Research
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università degli Studi di Trento
- Fondazione Umberto Veronesi
- Fondazione Pezcoller
- National Institutes of Health
- European Regional Development Fund