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

• Published in: International journal of molecular sciences Vol. 23; no. 6; p. 3203
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.03.2022; MDPI
• Subjects: Androgens; Androgens - pharmacology; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Benzamides - pharmacology; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Cancer therapies; COVID-19 - genetics; COVID-19 - metabolism; COVID-19 - virology; Cysts; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; Kinases; Male; Metastasis; Mice; Mutation; Nitriles - pharmacology; Organoids - metabolism; Patients; Phenylthiohydantoin - pharmacology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Virus - genetics; Receptors, Virus - metabolism; SARS-CoV-2 - metabolism; SARS-CoV-2 - physiology; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Spheroids; Transplantation, Heterologous; Tumors; Virus Internalization; prostate cancer San Diego 1; SARS-CoV-2; basal-luminal-like hybrid; bone metastatic prostate cancer; dormant; transmembrane protease serine 2; patient-derived xenograft; androgen pathway directed therapy; patient-derived organoids; angiotensin-converting enzyme 2; enzalutamide
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23063203

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.