Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer
Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of <i>RARG</i> uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.
Authors
- Gerhardt Attard (ORCID: https://orcid.org/0000-0002-4811-7983)
- Steven Joniau (ORCID: https://orcid.org/0000-0003-3195-9890)
- Wilbert Zwart (ORCID: https://orcid.org/0000-0002-9823-7289)
- Joshua M. Lang (ORCID: https://orcid.org/0000-0002-0943-8872)
- Emmanuel S. Antonarakis (ORCID: https://orcid.org/0000-0003-0031-9655)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Paari Murugan
- Braedan M. McCluskey (ORCID: https://orcid.org/0000-0001-6423-7048)
- Hannah E. Bergom (ORCID: https://orcid.org/0000-0003-2157-6562)
- Frank Claessens (ORCID: https://orcid.org/0000-0002-8676-7709)
- Colleen L. Forster (ORCID: https://orcid.org/0000-0001-5593-882X)
- John T. Lafin (ORCID: https://orcid.org/0000-0003-2335-8999)
- Wout Devlies (ORCID: https://orcid.org/0000-0003-0725-6300)
- Yinjie Qiu (ORCID: https://orcid.org/0000-0002-0584-0688)
- Himisha Beltran (ORCID: https://orcid.org/0000-0003-3259-2226)
- Ella Boytim (ORCID: https://orcid.org/0009-0007-8062-6431)
- Atef Ali (ORCID: https://orcid.org/0009-0004-8643-7744)
- Samuel P. Pitzen (ORCID: https://orcid.org/0000-0001-6556-0461)
- Simon Linder (ORCID: https://orcid.org/0000-0002-3315-305X)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Scott M. Dehm (ORCID: https://orcid.org/0000-0002-7827-5579)
- Weijie Zhang (ORCID: https://orcid.org/0000-0002-8978-8310)
- Douglas W. Strand (ORCID: https://orcid.org/0000-0002-0746-927X)
- R. Stephanie Huang (ORCID: https://orcid.org/0000-0002-9862-0368)
- Yuzhuo Z. Wang (ORCID: https://orcid.org/0000-0002-9749-8591)
- Mazlina Ismail (ORCID: https://orcid.org/0000-0002-1514-3819)
- Justin H. Hwang (ORCID: https://orcid.org/0000-0003-1686-7103)
- Sarah A. Munro
- Conner J. Sessions (ORCID: https://orcid.org/0009-0004-3810-4099)
- Amber N. Rudenick
Institutions
- BC Cancer Agency (CA)
- University of Minnesota (US)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- University of British Columbia (CA)
- University of Washington (US)
- Cancer Institute (WIA) (IN)
- Pittsburgh Supercomputing Center (US)
- London Cancer (GB)
- Fred Hutch Cancer Center (US)
- University of Wisconsin Carbone Cancer Center (US)
- Oncode Institute (NL)
- Dana-Farber Cancer Institute (US)
- University of Minnesota Medical Center (US)
- The Prostate Centre (GB)
- University College London (GB)
- The University of Texas Southwestern Medical Center (US)
- KU Leuven (BE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1073/pnas.2415308122
- Citations
- 14
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 21.26
Funders
- National Cancer Institute