Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer

Amilcar Flores-Morales; Tobias B Bergmann; Charlotte Lavallee; Tanveer S. Batth; Dong Lin; Mads Lerdrup; Stine Friis; Anette Bartels; Gitte Kristensen; Agnieszka Krzyzanowska; Hui Xue; Ladan Fazli; Klaus Hansen; Martin A. Røder; Klaus Brasso; José M Moreira; Anders Bjartell; Yuzhuo Wang; Jesper V. Olsen; Colin C Collins; Diego Iglesias-Gato

doi:10.1158/1078-0432.ccr-18-0729

Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer

Amilcar Flores-Morales, Tobias B Bergmann, Charlotte Lavallee, Tanveer S. Batth, Dong Lin, Mads Lerdrup, Stine Friis, Anette Bartels, Gitte Kristensen, Agnieszka Krzyzanowska, Hui Xue, Ladan Fazli, Klaus Hansen, Martin A. Røder, Klaus Brasso, José M Moreira, Anders Bjartell, Yuzhuo Wang, Jesper V. Olsen, Colin C CollinsDiego Iglesias-Gato

21 Citations (Scopus)

Abstract

Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G ₁ , which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

Original language	English
Journal	Clinical Cancer Research
Volume	25
Issue number	2
Pages (from-to)	1-15
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.ccr-18-0729
Publication status	Published - 15 Jan 2019

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Flores-Morales, A., Bergmann, T. B., Lavallee, C., Batth, T. S., Lin, D., Lerdrup, M., Friis, S., Bartels, A., Kristensen, G., Krzyzanowska, A., Xue, H., Fazli, L., Hansen, K., Røder, M. A., Brasso, K., Moreira, J. M., Bjartell, A., Wang, Y., Olsen, J. V., ... Iglesias-Gato, D. (2019). Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer. Clinical Cancer Research, 25(2), 1-15. https://doi.org/10.1158/1078-0432.ccr-18-0729

Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer. / Flores-Morales, Amilcar; Bergmann, Tobias B; Lavallee, Charlotte et al.
In: Clinical Cancer Research, Vol. 25, No. 2, 15.01.2019, p. 1-15.

Research output: Contribution to journal › Journal article › Research › peer-review

Flores-Morales, A, Bergmann, TB, Lavallee, C, Batth, TS, Lin, D, Lerdrup, M, Friis, S, Bartels, A, Kristensen, G, Krzyzanowska, A, Xue, H, Fazli, L, Hansen, K , Røder, MA , Brasso, K , Moreira, JM, Bjartell, A, Wang, Y, Olsen, JV, Collins, CC & Iglesias-Gato, D 2019, 'Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer', Clinical Cancer Research, vol. 25, no. 2, pp. 1-15. https://doi.org/10.1158/1078-0432.ccr-18-0729

@article{658ec55beffd431b8e4c068abe4b3aca,

title = "Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer",

abstract = " Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G 1 , which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer. ",

author = "Amilcar Flores-Morales and Bergmann, {Tobias B} and Charlotte Lavallee and Batth, {Tanveer S.} and Dong Lin and Mads Lerdrup and Stine Friis and Anette Bartels and Gitte Kristensen and Agnieszka Krzyzanowska and Hui Xue and Ladan Fazli and Klaus Hansen and R{\o}der, {Martin A.} and Klaus Brasso and Moreira, {Jos{\'e} M} and Anders Bjartell and Yuzhuo Wang and Olsen, {Jesper V.} and Collins, {Colin C} and Diego Iglesias-Gato",

note = "Copyright {\textcopyright}2018, American Association for Cancer Research.",

year = "2019",

month = jan,

day = "15",

doi = "10.1158/1078-0432.ccr-18-0729",

language = "English",

volume = "25",

pages = "1--15",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research (A A C R)",

number = "2",

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TY - JOUR

T1 - Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer

AU - Flores-Morales, Amilcar

AU - Bergmann, Tobias B

AU - Lavallee, Charlotte

AU - Batth, Tanveer S.

AU - Lin, Dong

AU - Lerdrup, Mads

AU - Friis, Stine

AU - Bartels, Anette

AU - Kristensen, Gitte

AU - Krzyzanowska, Agnieszka

AU - Xue, Hui

AU - Fazli, Ladan

AU - Hansen, Klaus

AU - Røder, Martin A.

AU - Brasso, Klaus

AU - Moreira, José M

AU - Bjartell, Anders

AU - Wang, Yuzhuo

AU - Olsen, Jesper V.

AU - Collins, Colin C

AU - Iglesias-Gato, Diego

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G 1 , which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

AB - Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G 1 , which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

U2 - 10.1158/1078-0432.ccr-18-0729

DO - 10.1158/1078-0432.ccr-18-0729

M3 - Journal article

C2 - 30274982

SN - 1078-0432

VL - 25

SP - 1

EP - 15

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 2

ER -

Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer

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