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

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Harvard

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, bind 25, nr. 2, s. 595-608. https://doi.org/10.1158/1078-0432.CCR-18-0729

APA

CBE

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. 25(2):595-608. https://doi.org/10.1158/1078-0432.CCR-18-0729

MLA

Vancouver

Author

Flores-Morales, Amilcar ; Bergmann, Tobias B ; Lavallee, Charlotte ; Batth, Tanveer S ; Lin, Dong ; Lerdrup, Mads ; Friis, Stine ; Bartels, Anette ; Kristensen, Gitte ; Krzyzanowska, Agnieszka ; Xue, Hui ; Fazli, Ladan ; Hansen, Klaus ; Røder, M Andreas ; Brasso, Klaus ; Moreira, José M ; Bjartell, Anders ; Wang, Yuzhuo ; Olsen, Jesper V ; Collins, Colin C ; Iglesias-Gato, Diego. / Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer. I: Clinical Cancer Research. 2019 ; Bind 25, Nr. 2. s. 595-608.

Bibtex

@article{813191a921c1478da3bd532fd5d21b4c,
title = "Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer",
abstract = "PURPOSE: 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 were correlated to the expression changes in vivoto investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.RESULTS: An average of 4881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell cycle regulation and DNA repair were found upregulated 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 REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST regulated gene Secretagogin (SCGN), correlated with in 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 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, {M Andreas} 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 = "{\circledC}2018 American Association for Cancer Research.",
year = "2019",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-18-0729",
language = "English",
volume = "25",
pages = "595--608",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",
number = "2",

}

RIS

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, M Andreas

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

N1 - ©2018 American Association for Cancer Research.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - PURPOSE: 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 were correlated to the expression changes in vivoto investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.RESULTS: An average of 4881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell cycle regulation and DNA repair were found upregulated 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 REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST regulated gene Secretagogin (SCGN), correlated with in 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 p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

AB - PURPOSE: 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 were correlated to the expression changes in vivoto investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.RESULTS: An average of 4881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell cycle regulation and DNA repair were found upregulated 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 REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST regulated gene Secretagogin (SCGN), correlated with in 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 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

VL - 25

SP - 595

EP - 608

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -

ID: 55534447