Proceedings of the National Academy of Sciences of the United States of America · 2025
Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer.
СтатьяСравнительное исследованиеНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.