Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer
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Published:2022-08-13
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Al-Nakouzi NaderORCID, Wang Chris Kedong, Oo Htoo Zarni, Nelepcu IrinaORCID, Lallous Nada, Spliid Charlotte B., Khazamipour Nastaran, Lo Joey, Truong Sarah, Collins Colin, Hui Desmond, Esfandnia Shaghayegh, Adomat Hans, Clausen Thomas Mandel, Gustavsson Tobias, Choudhary Swati, Dagil RobertORCID, Corey EvaORCID, Wang Yuzhuo, Chauchereau Anne, Fazli Ladan, Esko Jeffrey D., Salanti Ali, Nelson Peter S., Gleave Martin E., Daugaard MadsORCID
Abstract
AbstractLineage 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.
Funder
Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre Prostate Cancer Canada Mitacs
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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