Reformation of the Chondroitin Sulfate Glycocalyx Enables Progression of AR-independent Prostate Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Aug 13

PMID 35963852

Authors

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

Mads Daugaard

Affiliations

Soon will be listed here.

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.

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