N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Adeline Berger, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, Adnan Ahmed, Etienne Dardenne, Xiaodong Lu, Inah Hwang, Alyssa M. Bagadion, Andrea Sboner, Olivier Elemento, Jihye Paik, Jindan Yu, Christopher E. Barbieri, Noah Dephoure, Himisha Beltran, David S. Rickman*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)3924-3940
Number of pages17
JournalJournal of Clinical Investigation
Volume129
Issue number9
DOIs
StatePublished - Sep 3 2019

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Epigenomics
Prostatic Neoplasms
Androgen Receptors
Histone Code
Organoids
Castration
Transcriptome
Genes
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Berger, A., Brady, N. J., Bareja, R., Robinson, B., Conteduca, V., Augello, M. A., ... Rickman, D. S. (2019). N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. Journal of Clinical Investigation, 129(9), 3924-3940. https://doi.org/10.1172/JCI127961
Berger, Adeline ; Brady, Nicholas J. ; Bareja, Rohan ; Robinson, Brian ; Conteduca, Vincenza ; Augello, Michael A. ; Puca, Loredana ; Ahmed, Adnan ; Dardenne, Etienne ; Lu, Xiaodong ; Hwang, Inah ; Bagadion, Alyssa M. ; Sboner, Andrea ; Elemento, Olivier ; Paik, Jihye ; Yu, Jindan ; Barbieri, Christopher E. ; Dephoure, Noah ; Beltran, Himisha ; Rickman, David S. / N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 9. pp. 3924-3940.
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abstract = "Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.",
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Berger, A, Brady, NJ, Bareja, R, Robinson, B, Conteduca, V, Augello, MA, Puca, L, Ahmed, A, Dardenne, E, Lu, X, Hwang, I, Bagadion, AM, Sboner, A, Elemento, O, Paik, J, Yu, J, Barbieri, CE, Dephoure, N, Beltran, H & Rickman, DS 2019, 'N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer', Journal of Clinical Investigation, vol. 129, no. 9, pp. 3924-3940. https://doi.org/10.1172/JCI127961

N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. / Berger, Adeline; Brady, Nicholas J.; Bareja, Rohan; Robinson, Brian; Conteduca, Vincenza; Augello, Michael A.; Puca, Loredana; Ahmed, Adnan; Dardenne, Etienne; Lu, Xiaodong; Hwang, Inah; Bagadion, Alyssa M.; Sboner, Andrea; Elemento, Olivier; Paik, Jihye; Yu, Jindan; Barbieri, Christopher E.; Dephoure, Noah; Beltran, Himisha; Rickman, David S.

In: Journal of Clinical Investigation, Vol. 129, No. 9, 03.09.2019, p. 3924-3940.

Research output: Contribution to journalArticle

TY - JOUR

T1 - N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

AU - Berger, Adeline

AU - Brady, Nicholas J.

AU - Bareja, Rohan

AU - Robinson, Brian

AU - Conteduca, Vincenza

AU - Augello, Michael A.

AU - Puca, Loredana

AU - Ahmed, Adnan

AU - Dardenne, Etienne

AU - Lu, Xiaodong

AU - Hwang, Inah

AU - Bagadion, Alyssa M.

AU - Sboner, Andrea

AU - Elemento, Olivier

AU - Paik, Jihye

AU - Yu, Jindan

AU - Barbieri, Christopher E.

AU - Dephoure, Noah

AU - Beltran, Himisha

AU - Rickman, David S.

PY - 2019/9/3

Y1 - 2019/9/3

N2 - Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

AB - Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

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Berger A, Brady NJ, Bareja R, Robinson B, Conteduca V, Augello MA et al. N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. Journal of Clinical Investigation. 2019 Sep 3;129(9):3924-3940. https://doi.org/10.1172/JCI127961