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Proteogenomic chara...
Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer
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- Flores-Morales, Amilcar (author)
- University of Copenhagen,Danish Cancer Society
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- Bergmann, Tobias B. (author)
- Danish Cancer Society,University of Copenhagen
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- Lavallee, Charlotte (author)
- University of Copenhagen,Danish Cancer Society
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- Batth, Tanveer S. (author)
- University of Copenhagen
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- Lin, Dong (author)
- University of British Columbia
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- Lerdrup, Mads (author)
- University of Copenhagen
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- Friis, Stine (author)
- Danish Cancer Society,University of Copenhagen
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- Bartels, Anette (author)
- Danish Cancer Society,University of Copenhagen
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- Kristensen, Gitte (author)
- University of Copenhagen,Copenhagen University Hospital
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- Krzyzanowska, Agnieszka (author)
- Lund University,Lunds universitet,Urologisk cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Urological cancer, Malmö,Lund University Research Groups
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- Xue, Hui (author)
- University of British Columbia
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- Fazli, Ladan (author)
- University of British Columbia
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- Hansen, Klaus H. (author)
- University of Copenhagen
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- Røder, Martin A. (author)
- Copenhagen University Hospital,University of Copenhagen
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- Brasso, Klaus (author)
- Copenhagen University Hospital,University of Copenhagen
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- Moreira, Jose M. (author)
- Danish Cancer Society,University of Copenhagen
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- Bjartell, Anders (author)
- Lund University,Lunds universitet,Urologisk cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Urological cancer, Malmö,Lund University Research Groups
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- Wang, Yuzhuo (author)
- University of British Columbia
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- Olsen, Jesper V. (author)
- University of Copenhagen
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- Collins, Colin C. (author)
- University of British Columbia
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- Iglesias-Gato, Diego (author)
- University of Copenhagen,Danish Cancer Society
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(creator_code:org_t)
- 2019
- 2019
- English 14 s.
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In: Clinical Cancer Research. - 1078-0432. ; 25:2, s. 595-608
- Related links:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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Abstract
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- 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 G1, 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- By the author/editor
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Flores-Morales, ...
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Bergmann, Tobias ...
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Lavallee, Charlo ...
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Batth, Tanveer S ...
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Lin, Dong
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Lerdrup, Mads
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show more...
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Friis, Stine
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Bartels, Anette
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Kristensen, Gitt ...
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Krzyzanowska, Ag ...
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Xue, Hui
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Fazli, Ladan
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Hansen, Klaus H.
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Røder, Martin A.
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Brasso, Klaus
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Moreira, Jose M.
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Bjartell, Anders
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Wang, Yuzhuo
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Olsen, Jesper V.
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Collins, Colin C ...
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Iglesias-Gato, D ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Clinical Cancer ...
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Lund University