Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Samuel P. Pitzen
Masonic Cancer Center, University of Minnesota
Amber N. Rudenick
Masonic Cancer Center, University of Minnesota
Yinjie Qiu
Minnesota Supercomputing Institute, University of Minnesota
Weijie Zhang
Sarah A. Munro
Minnesota Supercomputing Institute, University of Minnesota
Braedan M. McCluskey
Minnesota Supercomputing Institute, University of Minnesota
Colleen Forster
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School
Hannah E. Bergom
Division of Hematology, Oncology and Transplantation, University of Minnesota
Atef Ali
Division of Hematology, Oncology and Transplantation, University of Minnesota
Ella Boytim
Division of Hematology, Oncology and Transplantation, University of Minnesota
John T. Lafin
Department of Urology, University of Texas Southwestern Medical Center
Simon Linder
Division on Oncogenomics, Oncode Institute, The Netherlands Cancer Institute
Mazlina Ismail
Department of Oncology, University College London Cancer Institute
Wout Devlies
Department of Urology, University Hospitals Leuven
Conner J. Sessions
Department of Urology, University of Washington
Frank Claessens
Steven Joniau
Department of Urology, University Hospitals Leuven
Gerhardt Attard
Wilbert Zwart
Peter S. Nelson
Division of Hematology and Oncology, University of Washington, Fred Hutchinson Cancer Center
Eva Corey
Department of Urology, University of Washington
Yuzhuo Wang
Department of Urologic Sciences, Faculty of Medicine, Vancouver Prostate Centre, University of British Columbia
Joshua M. Lang
Department of Medicine, University of Wisconsin-Madison
Himisha Beltran
Douglas Strand
Department of Urology, University of Texas Southwestern Medical Center
Emmanuel S. Antonarakis
Masonic Cancer Center, University of Minnesota
Justin Hwang
Masonic Cancer Center, University of Minnesota
Paari Murugan
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School
R. Stephanie Huang
Masonic Cancer Center, University of Minnesota
Scott M. Dehm
Masonic Cancer Center, University of Minnesota