Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer

Nader Al-Nakouzi (), Chris Kedong Wang, Htoo Zarni Oo, Irina Nelepcu, Nada Lallous, Charlotte B. Spliid, Nastaran Khazamipour, Joey Lo, Sarah Truong, Colin Collins, Desmond Hui, Shaghayegh Esfandnia, Hans Adomat, Thomas Mandel Clausen, Tobias Gustavsson, Swati Choudhary, Robert Dagil, Eva Corey, Yuzhuo Wang, Anne Chauchereau, Ladan Fazli, Jeffrey D. Esko, Ali Salanti, Peter S. Nelson, Martin E. Gleave and Mads Daugaard ()
Additional contact information
Nader Al-Nakouzi: University of British Columbia
Chris Kedong Wang: University of British Columbia
Htoo Zarni Oo: University of British Columbia
Irina Nelepcu: University of British Columbia
Nada Lallous: University of British Columbia
Charlotte B. Spliid: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Nastaran Khazamipour: University of British Columbia
Joey Lo: University of British Columbia
Sarah Truong: University of British Columbia
Colin Collins: University of British Columbia
Desmond Hui: Vancouver Prostate Centre
Shaghayegh Esfandnia: Vancouver Prostate Centre
Hans Adomat: Vancouver Prostate Centre
Thomas Mandel Clausen: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Tobias Gustavsson: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Swati Choudhary: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Robert Dagil: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Eva Corey: University of Washington
Yuzhuo Wang: University of British Columbia
Anne Chauchereau: University of Paris-Saclay
Ladan Fazli: University of British Columbia
Jeffrey D. Esko: University of California San Diego
Ali Salanti: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Peter S. Nelson: University of Washington
Martin E. Gleave: University of British Columbia
Mads Daugaard: University of British Columbia

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.

Date: 2022
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DOI: 10.1038/s41467-022-32530-7

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