Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids

Sanghee Lee; Theresa R. Mendoza; Danielle N. Burner; Michelle T. Muldong; Christina C. N. Wu; Catalina Arreola-Villanueva; Abril Zuniga; Olga Greenburg; William Y. Zhu; Jamillah Murtadha; Evodie Koutouan; Naomi Pineda; Hao Pham; Sung-Gu Kang; Hyun Tae Kim; Gabriel Pineda; Kathleen M. Lennon; Nicholas A. Cacalano; Catriona H. M. Jamieson; Christopher J. Kane; Anna A. Kulidjian; Terry Gaasterland; Christina A. M. Jamieson

doi:10.3390/ijms23063203

International Journal of Molecular Sciences (Mar 2022)

Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids

Sanghee Lee,
Theresa R. Mendoza,
Danielle N. Burner,
Michelle T. Muldong,
Christina C. N. Wu,
Catalina Arreola-Villanueva,
Abril Zuniga,
Olga Greenburg,
William Y. Zhu,
Jamillah Murtadha,
Evodie Koutouan,
Naomi Pineda,
Hao Pham,
Sung-Gu Kang,
Hyun Tae Kim,
Gabriel Pineda,
Kathleen M. Lennon,
Nicholas A. Cacalano,
Catriona H. M. Jamieson,
Christopher J. Kane,
Anna A. Kulidjian,
Terry Gaasterland,
Christina A. M. Jamieson

Affiliations

Sanghee Lee: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Theresa R. Mendoza: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Danielle N. Burner: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Michelle T. Muldong: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Christina C. N. Wu: Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
Catalina Arreola-Villanueva: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Abril Zuniga: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Olga Greenburg: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
William Y. Zhu: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Jamillah Murtadha: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Evodie Koutouan: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Naomi Pineda: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Hao Pham: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Sung-Gu Kang: Department of Urology, Korea University College of Medicine, Seongbuk-Gu, Seoul 02841, Korea
Hyun Tae Kim: Department of Urology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
Gabriel Pineda: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Kathleen M. Lennon: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Nicholas A. Cacalano: Department of Radiation Oncology, University of California, Los Angeles, CA 90095, USA
Catriona H. M. Jamieson: Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
Christopher J. Kane: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA
Anna A. Kulidjian: Scripps MD Anderson Cancer Center, La Jolla, CA 92093, USA
Terry Gaasterland: Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093, USA
Christina A. M. Jamieson: Department of Urology, University of California San Diego, La Jolla, CA 92093, USA

DOI: https://doi.org/10.3390/ijms23063203
Journal volume & issue: Vol. 23, no. 6
p. 3203

Abstract

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Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.

Published in International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General); Science: Chemistry
Website: http://www.mdpi.com/journal/ijms

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