Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids
Sanghee Lee1,2,3, Theresa R Mendoza1,2, Danielle N Burner1,2
1Department of Urology, University of California San Diego, La Jolla, CA 92093, USA.
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.
Insights
Advanced prostate cancer (PCa) organoids reveal a new mechanism of treatment resistance. Enzalutamide induces a reversible dormant state, offering new therapeutic targets for castration-resistant prostate cancer.
Area of Science:
- Oncology
- Cancer Biology
- Prostate Cancer Research
Background:
- Advanced prostate cancer (PCa) with bone metastases is treated with androgen pathway directed therapy (APDT).
- APDT resistance leads to castration-resistant prostate cancer (CRPC).
- Understanding CRPC mechanisms requires better preclinical models that reflect tumor heterogeneity.
Purpose of the Study:
- To establish a preclinical model for studying APDT resistance in bone metastatic prostate cancer.
- To elucidate the mechanisms of castration resistance.
- To identify novel therapeutic targets for resistant prostate cancer.
Main Methods:
- Established patient-derived xenograft (PDX)-derived organoids (PDOs) from a bone metastatic PCa model (PCSD1).
- Cultured PDOs with or without androgen/enzalutamide to induce resistance.
- Utilized transcriptomics and Fucci2BL live cell cycle tracking for analysis.
Main Results:
- APDT-resistant PDOs emerged under androgen deprivation or enzalutamide treatment.
- Transcriptomics revealed altered neurogenic, steroidogenic, DNA repair, cell cycle, and SARS-CoV-2 host entry pathways (ACE2, TMPRSS2).
- Enzalutamide induced a reversible dormant cell state in 3D organoids, a novel finding at the single-cell level.
Conclusions:
- A new mechanism of castration resistance involves enzalutamide-induced dormancy and novel basal-luminal-like cells in bone metastatic PCa organoids.
- PDX-derived organoids provide a predictive platform for studying CRPC.
- These organoids can aid in developing therapies targeting dormant resistant cells and SARS-CoV-2 host factors.
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