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Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids.
Lee, Sanghee; Mendoza, Theresa R; Burner, Danielle N; Muldong, Michelle T; Wu, Christina C N; Arreola-Villanueva, Catalina; Zuniga, Abril; Greenburg, Olga; Zhu, William Y; Murtadha, Jamillah; Koutouan, Evodie; Pineda, Naomi; Pham, Hao; Kang, Sung-Gu; Kim, Hyun Tae; Pineda, Gabriel; Lennon, Kathleen M; Cacalano, Nicholas A; Jamieson, Catriona H M; Kane, Christopher J; Kulidjian, Anna A; Gaasterland, Terry; Jamieson, Christina A M.
  • Lee S; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Mendoza TR; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Burner DN; Rady Children's Hospital, San Diego, CA 92123, USA.
  • Muldong MT; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Wu CCN; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Arreola-Villanueva C; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Zuniga A; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Greenburg O; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Zhu WY; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Murtadha J; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Koutouan E; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Pineda N; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Pham H; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Kang SG; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Kim HT; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Pineda G; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Lennon KM; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Cacalano NA; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Jamieson CHM; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Kane CJ; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Kulidjian AA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Gaasterland T; Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
  • Jamieson CAM; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Int J Mol Sci ; 23(6)2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1742493
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Bone Neoplasms / Organoids / Gene Expression Regulation, Neoplastic / Gene Expression Profiling / Prostatic Neoplasms, Castration-Resistant Type of study: Prognostic study Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23063203

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Bone Neoplasms / Organoids / Gene Expression Regulation, Neoplastic / Gene Expression Profiling / Prostatic Neoplasms, Castration-Resistant Type of study: Prognostic study Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23063203