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

Author

Listed:
  • Nader Al-Nakouzi

    (University of British Columbia
    Vancouver Prostate Centre)

  • Chris Kedong Wang

    (University of British Columbia
    Vancouver Prostate Centre)

  • Htoo Zarni Oo

    (University of British Columbia
    Vancouver Prostate Centre)

  • Irina Nelepcu

    (University of British Columbia
    Vancouver Prostate Centre)

  • Nada Lallous

    (University of British Columbia
    Vancouver Prostate Centre)

  • Charlotte B. Spliid

    (University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
    University of California San Diego)

  • Nastaran Khazamipour

    (University of British Columbia
    Vancouver Prostate Centre)

  • Joey Lo

    (University of British Columbia
    Vancouver Prostate Centre)

  • Sarah Truong

    (University of British Columbia
    Vancouver Prostate Centre)

  • Colin Collins

    (University of British Columbia
    Vancouver Prostate Centre)

  • 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
    University of California San Diego)

  • Tobias Gustavsson

    (University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
    VAR2pharmaceuticals Ole Maaløes Vej 3)

  • Swati Choudhary

    (University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
    VAR2pharmaceuticals Ole Maaløes Vej 3)

  • Robert Dagil

    (University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
    VAR2pharmaceuticals Ole Maaløes Vej 3)

  • Eva Corey

    (University of Washington)

  • Yuzhuo Wang

    (University of British Columbia
    Vancouver Prostate Centre)

  • Anne Chauchereau

    (University of Paris-Saclay)

  • Ladan Fazli

    (University of British Columbia
    Vancouver Prostate Centre)

  • 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
    Fred Hutchinson Cancer Centre)

  • Martin E. Gleave

    (University of British Columbia
    Vancouver Prostate Centre)

  • Mads Daugaard

    (University of British Columbia
    Vancouver Prostate Centre)

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.

Suggested Citation

  • 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 Esf, 2022. "Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32530-7
    DOI: 10.1038/s41467-022-32530-7
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    References listed on IDEAS

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