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Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications
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 enter...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234014/ https://www.ncbi.nlm.nih.gov/pubmed/35082166 http://dx.doi.org/10.1158/1541-7786.MCR-21-1037 |
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author | Dong, Xin Xue, Hui Mo, Fan Lin, Yen-yi Lin, Dong Wong, Nelson K.Y. Sun, Yingqiang Wilkinson, Scott Ku, Anson T. Hao, Jun Ci, Xinpei Wu, Rebecca Haegert, Anne Silver, Rebecca Taplin, Mary-Ellen Balk, Steven P. Alumkal, Joshi J. Sowalsky, Adam G. Gleave, Martin Collins, Colin Wang, Yuzhuo |
author_facet | Dong, Xin Xue, Hui Mo, Fan Lin, Yen-yi Lin, Dong Wong, Nelson K.Y. Sun, Yingqiang Wilkinson, Scott Ku, Anson T. Hao, Jun Ci, Xinpei Wu, Rebecca Haegert, Anne Silver, Rebecca Taplin, Mary-Ellen Balk, Steven P. Alumkal, Joshi J. Sowalsky, Adam G. Gleave, Martin Collins, Colin Wang, Yuzhuo |
author_sort | Dong, Xin |
collection | PubMed |
description | 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. IMPLICATIONS: 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. |
format | Online Article Text |
id | pubmed-9234014 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-92340142022-06-27 Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications Dong, Xin Xue, Hui Mo, Fan Lin, Yen-yi Lin, Dong Wong, Nelson K.Y. Sun, Yingqiang Wilkinson, Scott Ku, Anson T. Hao, Jun Ci, Xinpei Wu, Rebecca Haegert, Anne Silver, Rebecca Taplin, Mary-Ellen Balk, Steven P. Alumkal, Joshi J. Sowalsky, Adam G. Gleave, Martin Collins, Colin Wang, Yuzhuo Mol Cancer Res Cell Fate Decisions 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. IMPLICATIONS: 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. American Association for Cancer Research 2022-05-04 2022-01-26 /pmc/articles/PMC9234014/ /pubmed/35082166 http://dx.doi.org/10.1158/1541-7786.MCR-21-1037 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Cell Fate Decisions Dong, Xin Xue, Hui Mo, Fan Lin, Yen-yi Lin, Dong Wong, Nelson K.Y. Sun, Yingqiang Wilkinson, Scott Ku, Anson T. Hao, Jun Ci, Xinpei Wu, Rebecca Haegert, Anne Silver, Rebecca Taplin, Mary-Ellen Balk, Steven P. Alumkal, Joshi J. Sowalsky, Adam G. Gleave, Martin Collins, Colin Wang, Yuzhuo Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications |
title | Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications |
title_full | Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications |
title_fullStr | Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications |
title_full_unstemmed | Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications |
title_short | Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications |
title_sort | modeling androgen deprivation therapy–induced prostate cancer dormancy and its clinical implications |
topic | Cell Fate Decisions |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234014/ https://www.ncbi.nlm.nih.gov/pubmed/35082166 http://dx.doi.org/10.1158/1541-7786.MCR-21-1037 |
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