Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer

Elena S. Martens-Uzunova, Gina D. Kusuma, Stefania Crucitta, Hong Kiat Lim, Crystal Cooper, James E. Riches, Arun Azad, Takahiro Ochiya, Glen M. Boyle, Melissa C. Southey, Marzia Del Re, Rebecca Lim, Grant A. Ramm, Guido W. Jenster, Carolina Soekmadji*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma-derived circulating vesicles consisting of CD9 and double-positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S-EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S-EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S-EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S-EVs. A total of 543 small RNAs were found to be regulated by androgens including miR-19-3p and miR-361-5p. Analysis of S-EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration-resistant prostate cancer.

Original languageEnglish
Article numbere12136
JournalJournal of Extracellular Vesicles
Volume10
Issue number10
DOIs
Publication statusPublished - 18 Aug 2021

Bibliographical note

Funding Information:
The authors would like to thank Prof Neil Bander (Weill Cornell Medicine, USA) for providing humanised J591 PSMA antibody for detection of PSMA+ S-EVs using Exoview and Prof Leland W. Chung (Cedars-Sinai, MD Anderson Cancer Centre, USA) for C42B cells. We acknowledge the facilities and the scientific and technical assistance from the Microscopy Australia (MA) supported facility at the Central Analytical Research Facility (CARF), Institute for Future Environments, Queensland University of Technology. We acknowledge the European Community's Seventh Framework Program (FP7/2007-2013) grant agreement No HEALTH-F2-2007-201438 project ProsperR that generated the small RNA microarray expression signatures used in this work. The authors would also like to thank Prof Ana Claudia Trocoli Torrecilhas (Federal University of Sao Paulo), Dr Gavin Higgins (Victorian Cancer Biobank, VCB), Dr Sriganesh Srihari (QIMR Berghofer) and Dr Clayton Deighan (Nanoview) for their advice and assistance. The VCB through the Cancer Council Victoria as Lead Agency is supported by the Victorian Government through the Victorian Cancer Agency, a business unit of the Department of Health and Human Services. Most importantly, we thank all the patients who contributed to this study by donating blood samples. This work was supported by the Office of the Assistant Secretary of Defence for Health Affairs through the US Department of Defence Congressionally Directed Medical Research Program Prostate Cancer Research Program Idea Development Award [Number: W81XWH-16-1-0736] for CS; through the ?IMMPROVE? consortium, sponsored by an Alpe d'HuZes grant of the Dutch Cancer Society (grant #EMCR2015-8022) for ESMU and GWJ; and an EUR fellowship 2018-CvB/RE/PJ/RA00279215 for ESMU. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the DoD.

Funding Information:
The authors would like to thank Prof Neil Bander (Weill Cornell Medicine, USA) for providing humanised J591 PSMA antibody for detection of PSMA+ S‐EVs using Exoview and Prof Leland W. Chung (Cedars‐Sinai, MD Anderson Cancer Centre, USA) for C42B cells. We acknowledge the facilities and the scientific and technical assistance from the Microscopy Australia (MA) supported facility at the Central Analytical Research Facility (CARF), Institute for Future Environments, Queensland University of Technology. We acknowledge the European Community's Seventh Framework Program (FP7/2007‐2013) grant agreement No HEALTH‐F2‐2007‐201438 project ProsperR that generated the small RNA microarray expression signatures used in this work. The authors would also like to thank Prof Ana Claudia Trocoli Torrecilhas (Federal University of Sao Paulo), Dr Gavin Higgins (Victorian Cancer Biobank, VCB), Dr Sriganesh Srihari (QIMR Berghofer) and Dr Clayton Deighan (Nanoview) for their advice and assistance. The VCB through the Cancer Council Victoria as Lead Agency is supported by the Victorian Government through the Victorian Cancer Agency, a business unit of the Department of Health and Human Services. Most importantly, we thank all the patients who contributed to this study by donating blood samples.

Funding Information:
This work was supported by the Office of the Assistant Secretary of Defence for Health Affairs through the US Department of Defence Congressionally Directed Medical Research Program Prostate Cancer Research Program Idea Development Award [Number: W81XWH‐16‐1‐0736] for CS; through the “IMMPROVE” consortium, sponsored by an Alpe d'HuZes grant of the Dutch Cancer Society (grant #EMCR2015‐8022) for ESMU and GWJ; and an EUR fellowship 2018‐CvB/RE/PJ/RA00279215 for ESMU. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the DoD.

Publisher Copyright:
© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles

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