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

Nader Al-Nakouzi (1) , Chris Kedong Wang , Htoo Zarni Oo , Irina Nelepcu , Nada Lallous (2) , Charlotte Spliid , Nastaran Khazamipour , Joey Lo , Sarah Truong , Colin Collins (3, 4) , Desmond Hui , Shaghayegh Esfandnia , Hans Adomat , Thomas Mandel Clausen , Tobias Gustavsson , Swati Choudhary , Robert Dagil , Eva Corey , Yuzhuo Wang , Anne Chauchereau (5, 6) , Ladan Fazli , Jeffrey Esko , Ali Salanti , Peter Nelson , Martin Gleave (1) , Mads Daugaard (1)

1 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia
2 University of British Columbia [Vancouver]
3 Vancouver Prostate Cancer Centre
4 Department of Urologic Sciences
5 U981 - Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse
6 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie

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.

Domaines: Sciences du Vivant [q-bio]

Nader Al-Nakouzi, Chris Kedong Wang, Htoo Zarni Oo, Irina Nelepcu, Nada Lallous, et al.. Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer. Nature Communications, 2022, 13 (1), pp.4760. ⟨10.1038/s41467-022-32530-7⟩. ⟨hal-04478751⟩