Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Mark M. Pomerantz, Xintao Qiu, Yanyun Zhu, David Y. Takeda, Wenting Pan, Sylvan C. Baca, Alexander Gusev, Keegan D. Korthauer, Tesa M. Severson, Gavin Ha, Srinivas R. Viswanathan, Ji Heui Seo, Holly M. Nguyen, Baohui Zhang, Bogdan Pasaniuc, Claudia Giambartolomei, Sarah A. Alaiwi, Connor A. Bell, Edward P. O’Connor, Matthew S. ChabotDavid R. Stillman, Rosina Lis, Alba Font-Tello, Lewyn Li, Paloma Cejas, Andries M. Bergman, Joyce Sanders, Henk G. van der Poel, Simon A. Gayther, Kate Lawrenson, Marcos A.S. Fonseca, Jessica Reddy, Rosario I. Corona, Gleb Martovetsky, Brian Egan, Toni Choueiri, Leigh Ellis, Isla P. Garraway, Gwo Shu Mary Lee, Eva Corey, Henry W. Long, Wilbert Zwart, Matthew L. Freedman (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

143 Citations (Scopus)

Abstract

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Original languageEnglish
Pages (from-to)790-799
Number of pages10
JournalNature Genetics
Volume52
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

Funding

We thank M. Brown (DFCI) and members of the Center for Functional Cancer Epigenetics at DFCI for useful discussions and technical assistance. We also thank the NKI Core Facility Molecular Pathology and Biobanking for technical assistance and tissue processing, and the NKI Genomics Core Facility for the Illumina sequencing analyses. We thank K. Schuurman, D. Sondheim and J. Conner for technical support. We also thank P. Nelson and C. Pritchard for their contributions to the dataset. This work was supported by R. and N. Milikowsky (to M.M.P.); a Prostate Cancer Foundation Challenge Award (to M.M.P. and M.L.F.); NIH grant nos. R01GM107427 and R01CA193910 (to M.L.F.); the H.L. Snyder Medical Research Foundation (to M.L.F.); Department of Defense (DOD) grant no.W81XWH-19-1-0565 (to M.L.F., M.M.P. and W.Z.); a VIDI grant from the Netherlands Organisation for Scientific Research (to W.Z.); the Dutch Cancer Society/Alpe d’HuZes (10084) and Oncode Institute (to W.Z.); NIH grant no. K08 13 CA218530 (to D.Y.T.); the Jean Perkins Foundation; the Prostate Cancer Foundation; the STOP Cancer Foundation; Department of Defense (DOD) grant no. W81XWH-14-1-0273; National Cancer Institute/NIH grant no. P50CA092131 (to I.P.G.); the PNW Prostate Cancer SPORE no. P50 CA097186; DOD grant no. W81XWH-17-1-0415; and grant no. P01 CA163227. The IPCR supported the establishment and generation of the LuCaP PDXs models. We thank the patients who generously donated the tissue that made this research possible.

FundersFunder number
KWF Dutch Cancer Society10084
National Cancer Institute/NIHP50 CA097186, W81XWH-17-1-0415
Oncode InstituteK08 13 CA218530
Snyder Medical Research Foundation
National Institutes of HealthR01GM107427
U.S. Department of Defense
National Cancer InstituteR01CA193910, P50CA092131
Prostate Cancer Foundation
Stop CancerW81XWH-14-1-0273
Jean Perkins Foundation
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Alpe d’Huzes

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