Abstract
The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies.
| Original language | English |
|---|---|
| Article number | 109625 |
| Journal | Cell Reports |
| Volume | 36 |
| Issue number | 10 |
| DOIs | |
| State | Published - 7 Sep 2021 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2021 The Authors
Funding
We are indebted to the PCa patients and families who contributed to this research. We thank Dr. Dawid Nowak (Weill Cornell Medicine [WCM]) and Dr. Jonathan E. Shoag (WCM) for helpful discussion. We thank Dr. Daphne Campigli Di Giammartino (WCM) for helpful advice regarding the ChIP-seq experiments. We thank Dr. Mark Rubin for mentorship and guidance in developing these projects and reagents. We thank the WCM Genomics Core Facility, the Biospecimen and Pathology Core of WCM SPORE in Prostate Cancer, and the Memorial Sloan Kettering Cancer Center cBioPortal. We are grateful to Drs. Eric Klein, Bruce J. Trock, R. Jeffrey Karnes, and Robert B. Den for patient data. This work was funded by the US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01 , R37CA215040 , and R01CA233650 , to C.E.B.), the Damon Runyon Cancer Research Foundation , the MetLife Foundation Family Clinical Investigator Award (to C.E.B.), and the Prostate Cancer Foundation (to M.A.A. and D.L.). We are indebted to the PCa patients and families who contributed to this research. We thank Dr. Dawid Nowak (Weill Cornell Medicine [WCM]) and Dr. Jonathan E. Shoag (WCM) for helpful discussion. We thank Dr. Daphne Campigli Di Giammartino (WCM) for helpful advice regarding the ChIP-seq experiments. We thank Dr. Mark Rubin for mentorship and guidance in developing these projects and reagents. We thank the WCM Genomics Core Facility, the Biospecimen and Pathology Core of WCM SPORE in Prostate Cancer, and the Memorial Sloan Kettering Cancer Center cBioPortal. We are grateful to Drs. Eric Klein, Bruce J. Trock, R. Jeffrey Karnes, and Robert B. Den for patient data. This work was funded by the US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01, R37CA215040, and R01CA233650, to C.E.B.), the Damon Runyon Cancer Research Foundation, the MetLife Foundation Family Clinical Investigator Award (to C.E.B.), and the Prostate Cancer Foundation (to M.A.A. and D.L.). Conceptualization, I.G. M.A.A. D.L. and C.E.B.; methodology, I.G. D.H. K.L. L.D.D. M.B. R.G. and D.I.; formal analysis, I.G. D.L. D.R.M. and C.D.G.; investigation, I.G.; validation, B.D.R. and F.K.; resources, E.D. L.D.D. C.E.B. and O.E.; writing – original draft, I.G. and C.E.B.; writing – review & editing, I.G. C.E.B. M.A.A. and D.L.; visualization, I.G.; supervision, C.E.B. and A.S.; funding acquisition, C.E.B. C.E.B. is co-inventor on a patent issued to Weill Medical College of Cornell University on SPOP mutations in PCa. E.D. is an employee of GenomeDx.
| Funders | Funder number |
|---|---|
| US NCI | R37CA215040, P50CA211024-01, R01CA233650 |
| WCM | |
| National Cancer Institute | P50CA211024 |
| Prostate Cancer Foundation | |
| MetLife Foundation | |
| Damon Runyon Cancer Research Foundation | |
| Weill Cornell Medical College |
