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Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration- Resistant Prostate Cancer Amilcar Flores-Morales1,2,3, Tobias B

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Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration- Resistant Prostate Cancer Amilcar Flores-Morales1,2,3, Tobias B Published OnlineFirst October 1, 2018; DOI: 10.1158/1078-0432.CCR-18-0729 Biology of Human Tumors Clinical Cancer Research Proteogenomic Characterization of Patient- Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration- Resistant Prostate Cancer Amilcar Flores-Morales1,2,3, Tobias B. Bergmann1,2, Charlotte Lavallee1,2, Tanveer S. Batth3, Dong Lin4, Mads Lerdrup5, Stine Friis1,2, Anette Bartels1,2, Gitte Kristensen6, Agnieszka Krzyzanowska7, Hui Xue4, Ladan Fazli4, Klaus H. Hansen5, Martin A. Røder6, Klaus Brasso6, Jose M. Moreira1,2, Anders Bjartell7, Yuzhuo Wang4, Jesper V. Olsen3, Colin C. Collins4, and Diego Iglesias-Gato1,2 Abstract Background: An increasing number of castration-resistant and elevated in NEPC, while the reduced levels of proteins prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) involved in mitochondrial functions suggested a prevalent features. NE prostate cancer (NEPC) has poor prognosis, and glycolytic metabolism of NEPC tumors. Integration of the its development is poorly understood. REST chromatin bound regions with expression changes Experimental Design: We applied mass spectrometry– indicated a direct role of REST in regulating neuronal gene based proteomics to a unique set of 17 prostate cancer expression in prostate cancer cells. Mechanistically, deple- patient–derived xenografts (PDX) to characterize the effects tion of REST led to cell-cycle arrest in G1, which could be of castration in vivo, and the proteome differences between rescued by p53 knockdown. Finally, the expression of the NEPC and prostate adenocarcinomas. Genome-wide profiling REST-regulated gene secretagogin (SCGN) correlated with of REST-occupied regions in prostate cancer cells was corre- an increased risk of suffering disease relapse after radical lated to the expression changes in vivo to investigate the role of prostatectomy. the transcriptional repressor REST in castration-induced NEPC Conclusions: This study presents the first deep characteri- differentiation. zation of the proteome of NEPC and suggests that concom- Results: An average of 4,881 proteins were identified and itant inhibition of REST and the p53 pathway would promote quantified from each PDX. Proteins related to neurogenesis, NEPC. We also identify SCGN as a novel prognostic marker in cell-cycle regulation, and DNA repair were found upregulated prostate cancer. Clin Cancer Res; 1–14. Ó2018 AACR. Introduction androgen receptor (AR) blockage and are driven by complex mechanisms that involve genetic, epigenetic, and posttranscrip- Death in prostate cancer patients mostly occurs after the devel- tional changes (1, 2). Extensive studies have been carried out to opment of castration-resistant metastatic disease (CRPC). Castra- identify tumor driving genetic alterations in CRPC, but a unified tion-resistant tumors develop after androgen ablation therapy or genetic model of disease progression is yet to emerge. Amplifi- cation of the AR gene locus or point mutations in the AR gene occurs in 60% of tumors that have been subjected to androgen 1Department of Drug Design and Pharmacology, Faculty of Health and Medical ablation therapy (3). The appearance of ligand-independent AR Sciences, University of Copenhagen, Copenhagen, Denmark. 2The Danish Can- fi 3 splice variants or AR posttranslational modi cation may also cer Society, Copenhagen, Denmark. Novo Nordisk Foundation Center for contribute to continued AR activation following castration (4). Protein Research, Faculty of Health and Medical Sciences, University of Copen- hagen, Copenhagen, Denmark. 4Vancouver Prostate Centre, University of British Other common genetic alterations in AR-expressing CRPC Columbia, Vancouver, British Columbia, Canada. 5Biotech Research and Inno- include heterozygous deletions of PTEN and, to a lesser extent, vation Center, University of Copenhagen, Copenhagen, Denmark. 6Copenhagen p53 inactivation or loss of Rb1 expression (5–8). Prostate Cancer Center, Department of Urology, Rigshospitalet, University of One recurrent cellular feature of CRPC is the presence of 7 Copenhagen, Copenhagen, Denmark. Department of Translational Medicine, carcinoma cells that exhibit a neuroendocrine phenotype. Neu- Division of Urological Cancers, Lund University, Lund, Sweden. roendocrine differentiation (NED) of prostate cells is frequently Note: Supplementary data for this article are available at Clinical Cancer associated with highly proliferative potential of tumors and Research Online (http://clincancerres.aacrjournals.org/). increased chemoresistance, and as a consequence understanding Corresponding Author: Diego Iglesias-Gato, University of Copenhagen, The the development of NED in CRCP can lead to the development of Danish Cancer Society. Strandboulevarden 49Strand, Copenhagen 2100, new therapeutic strategies for CRPC. Neuroendocrine prostate Denmark. Phone: 4535330640; Fax: 4535325001; E-mail: cancer (NEPC) constitutes a distinct class of castration-resistant [email protected] tumors characterized by the expression of neuronal markers such doi: 10.1158/1078-0432.CCR-18-0729 as Chromogranin A (CHGA), Synaptophysin (SYP), and neural Ó2018 American Association for Cancer Research. cell adhesion molecule (CD56; ref. 9). NEPCs show similarities to www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 1, 2018; DOI: 10.1158/1078-0432.CCR-18-0729 Flores-Morales et al. Radical prostatectomy tissue microarray Translational Relevance The study cohort is composed of a consecutive series of men The number of castration-resistant prostate tumors exhibit- (n ¼ 336) with clinically localized prostate cancer who underwent ing neuroendocrine features is increasing, due in part to the radical prostatectomy (RP) with curative intent from January 1, improvement of drugs targeting the androgen receptor. Neu- 2002, until December 31, 2005, at the Department of Urology, roendocrine prostate cancer has poor prognosis due to the Rigshospitalet, Copenhagen, Denmark. This study was approved limited efficacy of currently available therapies. In this study, by the Danish National Committee on Health Research Ethics for we provide the first deep characterization of the proteome of the Capital Region (Journal no.: H-6-2014-111). Biochemical castration-resistant neuroendocrine prostate cancer. Proteins failure (BF) was defined as PSA 0.2 mg/L. The collection of are the ultimate targets of most anticancer drugs; therefore, our data was approved by The Danish Data Protection Agency work constitutes a valuable resource for the development of (file#2006-1-6256). The validation cohort (Malmo)€ was previ- novel compounds targeting proteins with increased expression ously described (18, 21). All studies were conducted following the in these tumors. Moreover, we provide evidence that early principles of the Declaration of Helsinki. All participants gave expression of the neuron-specific protein secretagogin in early written or verbal consent. Verbal consent was documented by the stages of prostate cancer correlates with increased risk of physician in the patient journal. biochemical recurrence after radical prostatectomy and could be accounted for in patients managed with conservative pro- IHC and statistics tocols such as active surveillance. TMA sections were deparaffinized in xylene and rehydrated through graded ethanol- Antigen retrieval performed at pH6. IHC staining was performed using anti SCGN antibody (HPA006641, Sigma-Aldrich, diluted 1:250). The SCGN staining was quantified small-cell carcinoma of the prostate (SCCP), which accounts for by scoring the intensity and the percentage of stained tumor cells 0.5% to 2% of all primary prostatic malignancies (10). Patients (0 ¼ negative or positive only in scattered neuroendocrine pros- diagnosed with SCCP have poor prognosis, with a median sur- tate cells; 1 ¼ weak staining in less than 30% for the tumor cells; vival time ranging from 5 to 17.5 months and the 5-year survival 2 ¼ intense staining in less than 20% of the cells on a localized rate of 14.3% (11). Moreover, in patients with locally advanced focus; 3 ¼ moderated staining in more than 50% of the cells or tumors treated with androgen ablation therapy (alone or in a intense staining in less than 50%; 4 ¼ intense staining in more coadjuvant setting), and in patients with CRPC, the extent of NED than 50% of the cells). Of all cores obtained from the same has been shown to be an independent prognostic factor (12). specimen, the highest expression was selected. Scores 2 were The molecular mechanisms driving the development of NE considered as high SCGN expression. The association between tumors after castration therapy are yet to be fully understood. The SCGN expression and clinicopathologic variables was analyzed loss of AR expression, the identification of recurrent mutations in using c2 test or Fisher exact test for categorical variables and the tumor suppressor genes such as Rb1 and p53, and the amplifi- Mann–Whitney U test for continuous variables. The median time cation of genes such as Aurora Kinase A (AURKA) and MYCN are of follow-up was calculated using the reverse Kaplan–Meier thought to play important roles in NE transdifferentiation and the method (22). Follow-up for BF was calculated until the latest aggressiveness of prostate cancer (13–17). Additionally, we PSA measurement, whereas time to death was calculated until the recently demonstrated that inactivation
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