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

Autor: 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
Rok vydání: 2021
Předmět:
Male
Aging
Drug Resistance
Castration-Resistant
Mice
androgen pathway directed therapy
angiotensin-converting enzyme 2
basal-luminal-like hybrid
bone metastatic prostate cancer
dormant
enzalutamide
patient-derived organoids
patient-derived xenograft
prostate cancer San Diego 1
SARS-CoV-2
transmembrane protease serine 2
Receptors
2.1 Biological and endogenous factors
Aetiology
Spectroscopy
Cancer
Heterologous
Prostate Cancer
Serine Endopeptidases
General Medicine
Computer Science Applications
Virus
Gene Expression Regulation
Neoplastic
Organoids
Prostatic Neoplasms
Castration-Resistant
Benzamides
Androgens
Receptors
Virus
Angiotensin-Converting Enzyme 2
Urologic Diseases
Transplantation
Heterologous
Bone Neoplasms
Catalysis
Inorganic Chemistry
Clinical Research
Nitriles
Phenylthiohydantoin
Genetics
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
Transplantation
Neoplastic
Chemical Physics
Gene Expression Profiling
Organic Chemistry
COVID-19
Prostatic Neoplasms
Virus Internalization
Good Health and Well Being
Gene Expression Regulation
Drug Resistance
Neoplasm
Neoplasm
Other Biological Sciences
Other Chemical Sciences
Zdroj: International journal of molecular sciences, vol 23, iss 6
International Journal of Molecular Sciences; Volume 23; Issue 6; Pages: 3203
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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