Modeling Androgen Deprivation Therapy-Induced Prostate Cancer Dormancy and Its Clinical Implications.
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
04 05 2022
04 05 2022
Historique:
received:
08
12
2021
revised:
14
01
2022
accepted:
18
01
2022
pubmed:
28
1
2022
medline:
6
5
2022
entrez:
27
1
2022
Statut:
ppublish
Résumé
Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naïve or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors. We have established highly clinically relevant PDXs of ADT-induced dormant prostate cancer and identified two dormancy subtypes, leading to the development of a novel predicative gene signature that allows robust risk stratification of patients with prostate cancer to ADT or androgen-receptor pathway inhibitors.
Identifiants
pubmed: 35082166
pii: 1541-7786.MCR-21-1037
doi: 10.1158/1541-7786.MCR-21-1037
pmc: PMC9234014
mid: NIHMS1818290
doi:
Substances chimiques
Androgen Antagonists
0
Androgen Receptor Antagonists
0
Androgens
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
782-793Subventions
Organisme : NCI NIH HHS
ID : P50 CA186786
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011679
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251245
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011838
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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