Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration- resistant prostate cancer

• 成果类型: Article
• 署名作者: Pitzen, Samuel P.; Rudenick, Amber N.; Qiu, Yinjie; Zhang, Weijie; Munro, Sarah A.; Mccluskey, Braedan M.; Forster, Colleen; Bergom, Hannah E.; Ali, Atef; Boytim, Ella; Lafin, John T.; Linder, Simon; Ismail, Mazlina; Devlies, Wout; Sessions, Conner J.; Claessens, Frank; Joniau, Steven; Attard, Gerhardt; Zwart, Wilbert; Nelson, Peter S.; Corey, Eva; Wang, Yuzhuo; Lang, Joshua M.; Beltran, Himisha; Strand, Douglas; Antonarakis, Emmanuel S.; Hwang, Justin; Murugan, Paari; Huang, R. Stephanie; Dehm, Scott M.
• 署名单位: University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Minnesota System; University of Minnesota Twin Cities; University of Texas System; University of Texas Southwestern Medical Center; Netherlands Cancer Institute; University of London; University College London; KU Leuven; University Hospital Leuven; KU Leuven; University of Washington; University of Washington Seattle; KU Leuven; University of London; University College London; University College London Hospitals NHS Foundation Trust; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; University of British Columbia; British Columbia Cancer Agency; University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; University of Minnesota System; University of Minnesota Twin Cities
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13606
• DOI: 10.1073/pnas.2415308122
• 发表日期: 2025-02-11
• 关键词: retinoic acid; lineage plasticity; receptors; klf5; Heterogeneity; induction; therapy; tumors

摘要

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 RARG 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.