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

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  • Nader Al Nakouzi
  • Htoo Zarni Oo
  • Irina Nelepcu
  • Nada Lallous
  • Charlotte Bredo Spliid
  • Nastaran Khazamipour
  • Joey Lo
  • Sarah Truong
  • Colin Collins
  • Desmond Hui
  • Shaghayegh Esfandnia
  • Hans Adomat
  • Eva Corey
  • Yuzhou Wang
  • Anne Chauchereau
  • Ladan Fazli
  • Jeffrey D. Esko
  • Peter S Nelson
  • Martin Gleave
  • Mads Daugaard
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.
Original languageEnglish
Article number4760
JournalNature Communications
Publication statusPublished - 2022

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