Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer
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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; Batth, Tanveer S.; Lin, Dong; Lerdrup, Mads; Friis, Stine; Bartels, Anette; Kristensen, Gitte; Krzyzanowska, Agnieszka; Xue, Hui; Fazli, Ladan; Hansen, Klaus; Røder, Martin A.; Brasso, Klaus; Moreira, José M; Bjartell, Anders; Wang, Yuzhuo; Olsen, Jesper V.; Collins, Colin C; Iglesias-Gato, Diego.
In: Clinical Cancer Research, Vol. 25, No. 2, 2019, p. 1-15.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - Copyright ©2018, American Association for Cancer Research.
PY - 2019
Y1 - 2019
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
C2 - 30274982
VL - 25
SP - 1
EP - 15
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 2
ER -
ID: 203561806