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

Nader Al Nakouzi; Chris Kedong Wang; Htoo Zarni Oo; Irina Nelepcu; Nada Lallous; Charlotte Bredo 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; Yuzhou Wang; Anne Chauchereau; Ladan Fazli; Jeffrey D. Esko; Ali Salanti; Peter S Nelson; Martin Gleave; Mads Daugaard

doi:10.1038/s41467-022-32530-7

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

Nader Al Nakouzi, Chris Kedong Wang, Htoo Zarni Oo, Irina Nelepcu, Nada Lallous, Charlotte Bredo 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, Yuzhou Wang, Anne ChauchereauLadan Fazli, Jeffrey D. Esko, Ali Salanti, Peter S Nelson, Martin Gleave, Mads Daugaard

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	4760
Journal	Nature Communications
Volume	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-022-32530-7
Publication status	Published - 2022

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Al Nakouzi, N., Wang, C. K., Oo, H. Z., Nelepcu, I., Lallous, N., Spliid, C. B., Khazamipour, N., Lo, J., Truong, S., Collins, C., Hui, D., Esfandnia, S., Adomat, H., Clausen, T. M., Gustavsson, T., Choudhary, S., Dagil, R., Corey, E., Wang, Y., ... Daugaard, M. (2022). Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer. Nature Communications, 13, [4760]. https://doi.org/10.1038/s41467-022-32530-7

Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer. / Al Nakouzi, Nader; Wang, Chris Kedong; Oo, Htoo Zarni; Nelepcu, Irina; Lallous, Nada; Spliid, Charlotte Bredo; Khazamipour, Nastaran; Lo, Joey; Truong, Sarah; Collins, Colin; Hui, Desmond; Esfandnia, Shaghayegh; Adomat, Hans; Clausen, Thomas Mandel ; Gustavsson, Tobias ; Choudhary, Swati ; Dagil, Robert; Corey, Eva; Wang, Yuzhou; Chauchereau, Anne; Fazli, Ladan; Esko, Jeffrey D.; Salanti, Ali; Nelson, Peter S; Gleave, Martin; Daugaard, Mads.

In: Nature Communications, Vol. 13, 4760, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Al Nakouzi, N, Wang, CK, Oo, HZ, Nelepcu, I, Lallous, N, Spliid, CB, Khazamipour, N, Lo, J, Truong, S, Collins, C, Hui, D, Esfandnia, S, Adomat, H, Clausen, TM , Gustavsson, T , Choudhary, S , Dagil, R, Corey, E, Wang, Y, Chauchereau, A, Fazli, L, Esko, JD, Salanti, A, Nelson, PS, Gleave, M & Daugaard, M 2022, 'Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer', Nature Communications, vol. 13, 4760. https://doi.org/10.1038/s41467-022-32530-7

Al Nakouzi, Nader ; Wang, Chris Kedong ; Oo, Htoo Zarni ; Nelepcu, Irina ; Lallous, Nada ; Spliid, Charlotte Bredo ; Khazamipour, Nastaran ; Lo, Joey ; Truong, Sarah ; Collins, Colin ; Hui, Desmond ; Esfandnia, Shaghayegh ; Adomat, Hans ; Clausen, Thomas Mandel ; Gustavsson, Tobias ; Choudhary, Swati ; Dagil, Robert ; Corey, Eva ; Wang, Yuzhou ; Chauchereau, Anne ; Fazli, Ladan ; Esko, Jeffrey D. ; Salanti, Ali ; Nelson, Peter S ; Gleave, Martin ; Daugaard, Mads. / Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer. In: Nature Communications. 2022 ; Vol. 13.

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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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AU - Lallous, Nada

AU - Spliid, Charlotte Bredo

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AU - Lo, Joey

AU - Truong, Sarah

AU - Collins, Colin

AU - Hui, Desmond

AU - Esfandnia, Shaghayegh

AU - Adomat, Hans

AU - Clausen, Thomas Mandel

AU - Gustavsson, Tobias

AU - Choudhary, Swati

AU - Dagil, Robert

AU - Corey, Eva

AU - Wang, Yuzhou

AU - Chauchereau, Anne

AU - Fazli, Ladan

AU - Esko, Jeffrey D.

AU - Salanti, Ali

AU - Nelson, Peter S

AU - Gleave, Martin

AU - Daugaard, Mads

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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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