Basal-Luminal Hybrid Cells Emerge as a New Dormant, Androgen Pathway Directed Therapy-Resistant Population in Patient-Derived Prostate Cancer Organoids

Advanced prostate cancer (PCa) patients with bone metastases are treated standardly with Androgen Pathway Directed Therapy (APDT), however, they invariably become APDT-resistant. To  elucidate resistance mechanisms  and to provide more predictive  pre-clinical research platforms reflecting tumor heterogeneity, w e established organoids from patient-derived xenograft (PDX) models of bone metastatic prostate cancer. 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. These experiments demonstrated that PDOs can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry. Enzalutamide treatment decreased androgen receptor (AR) protein and induced dormant, hybrid basal-luminal cells as shown here for the first time in live organoids using the Fucci2BL fluorescent cell cycle tracker system.