400 results on '"Fazli, L."'
Search Results
52. Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice
- Author
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Moussavi, M, primary, Moshgabadi, N, additional, Fazli, L, additional, Leblanc, E, additional, Zhang, K, additional, Jia, W, additional, and Rennie, P S, additional
- Published
- 2011
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53. MP-03.04 The Combination Treatment of Bicalutamide Plus Carbidopa Significantly Enhances the in vivo Antitumor Activity on LNCaP Castration-resistant Prostate Cancer Xenograft Tumors Compared To Single Use of Each Drug
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Thomas, C., primary, Wafa, L., additional, Lamoureux, F., additional, Fazli, L., additional, Rennie, P., additional, and Gleave, M., additional
- Published
- 2011
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54. An evaluation of clusterin antisense inhibitor OGX-011 in combination with the second-generation antiandrogen MDV3100 in a castrate-resistant prostate cancer model.
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Matsumoto, H., primary, Kuruma, H., additional, Zoubeidi, A., additional, Fazli, L., additional, and Gleave, M. E., additional
- Published
- 2011
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55. A phase II study of preoperative figitumumab (F) in patients (pts) with localized prostate cancer (PCa).
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Chi, K. N., primary, Gleave, M. E., additional, Fazli, L., additional, Goldenberg, S. L., additional, So, A., additional, Kollmannsberger, C. K., additional, Murray, N., additional, Tinker, A., additional, Gualberto, A., additional, and Pollak, M. N., additional
- Published
- 2010
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56. Expression of LHRH receptors in prostate cancer cells prior to therapy, following castration, or following treatment with LHRH agonists
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Liu, S., primary, Schally, A. V., additional, Xiong, S., additional, Cote, R., additional, Hawes, D., additional, Fazli, L., additional, Gleave, M., additional, Cai, J., additional, Brands, F., additional, Engel, J., additional, and Pinski, J., additional
- Published
- 2009
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57. Five-year relapse-free survival and predictors of relapse following preoperative docetaxel and mitoxantrone for high-risk localized prostate cancer
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Rademacher, B. L., primary, Garzotto, M., additional, Higano, C. S., additional, O'Brien, C. A., additional, Janeba, N., additional, Fazli, L., additional, Lange, P. H., additional, Lieberman, S., additional, and Beer, T. M., additional
- Published
- 2009
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58. Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers
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Rajput, A. B, primary, Miller, M. A, additional, De Luca, A., additional, Boyd, N., additional, Leung, S., additional, Hurtado-Coll, A., additional, Fazli, L., additional, Jones, E. C, additional, Palmer, J. B, additional, Gleave, M. E, additional, Cox, M. E, additional, and Huntsman, D. G, additional
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- 2007
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59. Targeting and killing of prostate cancer cells using lentiviral constructs containing a sequence recognized by translation factor eIF4E and a prostate-specific promoter
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Yu, D, primary, Scott, C, additional, Jia, W W, additional, De Benedetti, A, additional, Williams, B J, additional, Fazli, L, additional, Wen, Y, additional, Gleave, M, additional, Nelson, C, additional, and Rennie, P S, additional
- Published
- 2005
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60. Significance of insulin-like growth factor binding protein-2 in the prognosis of breast cancer and promotion of accelerated growth and chemo-resistance in MDAMB-231 breast cancer model
- Author
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So, A. I., primary, Eigl, B., additional, Fazli, L., additional, Hunstman, D., additional, Ivanonv, N., additional, Pollak, M., additional, Dunn, S., additional, and Gleave, M., additional
- Published
- 2005
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61. A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of OGX-011, a 2'methoxyethyl phosphorothioate antisense to clusterin, in patients with prostate cancer prior to radical prostatectomy
- Author
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Chi, K. N., primary, Eisenhauer, E., additional, Fazli, L., additional, Jones, E. C., additional, Powers, J., additional, Ayers, D., additional, Goldenberg, S. L., additional, and Gleave, M. E., additional
- Published
- 2004
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62. Integrin-linked kinase, a promising cancer therapeutic target: biochemical and biological properties
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Yoganathan, N., primary, Yee, A., additional, Zhang, Z., additional, Leung, D., additional, Yan, J., additional, Fazli, L., additional, Kojic, D.L., additional, Costello, P.C., additional, Jabali, M., additional, Dedhar, S., additional, and Sanghera, J., additional
- Published
- 2002
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63. Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice.
- Author
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Moussavi, M, Moshgabadi, N, Fazli, L, Leblanc, E, Zhang, K, Jia, W, and Rennie, P S
- Subjects
FIBROBLAST growth factors ,ORNITHINE decarboxylase ,GENE expression ,PROSTATE cancer ,CANCER cells ,LABORATORY mice ,GREEN fluorescent protein - Abstract
In this study, we have taken advantage of over-expression of eukaryotic translation initiation factor 4E (eIF4E) in prostate cancer cells to design a viral-based targeting system of prostate cancer. Three different lengths of 5′-untranslated regions (5′UTRs) derived from either fibroblast growth factor-2 (FU-FGF2-GW) or ornithine decarboxylase (FU-ODC
149 -GW and FU-ODC274 -GW) were inserted upstream of enhanced green fluorescent protein (GFP) gene in a lentiviral backbone. Both nonmalignant control (PNT1B and BPH-1) and neoplastic (LNCaP, C4-2, DU145 and PC-3) prostate cell lines were transfected with each plasmid or virus alone, or in the presence of siRNA against eIF4E, and their expression was monitored via GFP protein levels. Two 5′UTRs (FU-FGF2-GW and FU-ODC-GW) were selected as being most sensitive to eIF4E status. Lentiviruses containing these sequences were injected directly into the prostates of PTEN−/− (tumor-bearing) and control mice. Immunofluorescence data and western blot analyses determined that a lentivirus containing a 5′UTR derived from FGF-2 is the best candidate for directing selective gene expression in the prostate tumors of PTEN−/− mice in vivo. This study demonstrates that judicious selection of a complex 5′UTR can enhance selective targeting of viral-based gene therapies for prostate cancer. [ABSTRACT FROM AUTHOR]- Published
- 2012
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64. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer.
- Author
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Chi KN, Eisenhauer E, Fazli L, Jones EC, Goldenberg SL, Powers J, Tu D, and Gleave ME
- Published
- 2005
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65. The BIRC6 gene as a novel target for therapy of prostate cancer: Dual targeting of inhibitors of apoptosis
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Iris Luk, S. U., Xue, H., Cheng, H., Lin, D., Gout, P. W., Fazli, L., Collins, C. C., Gleave, M. E., and Yuzhuo Wang
66. Separation of benign and malignant glands in prostatic adenocarcinoma
- Author
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Rashid, S., Fazli, L., Boag, A., Siemens, R., Purang Abolmaesumi, and Salcudean, S. E.
67. Long term deficiency of vitamin D in germ cell testicular cancer survivors
- Author
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Giovannella Palmieri, Lucia Nappi, Martin E. Gleave, Sabino De Placido, Margaret Ottaviano, Pasquale Rescigno, Vincenzo Damiano, Ladan Fazli, Nappi, L., Ottaviano, M., Rescigno, P., Fazli, L., Gleave, M. E., Damiano, V., De Placido, S., and Palmieri, G.
- Subjects
Quality of life ,medicine.medical_specialty ,long term side effects ,medicine.medical_treatment ,Long term side effect ,testicular cancer survivors ,030209 endocrinology & metabolism ,Calcitriol receptor ,Gastroenterology ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Testicular cancer ,Testicular cancer survivor ,Internal medicine ,Vitamin D and neurology ,Medicine ,Vitamin D ,Testosterone ,Chemotherapy ,business.industry ,Seminoma ,medicine.disease ,Oncology ,030220 oncology & carcinogenesis ,Germ cell tumors ,business ,Research Paper - Abstract
// Lucia Nappi 1 , Margaret Ottaviano 2 , Pasquale Rescigno 2, 3 , Ladan Fazli 1 , Martin E. Gleave 1 , Vincenzo Damiano 2 , Sabino De Placido 4 and Giovannella Palmieri 2 1 Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada 2 Department of Medicine and Surgery, Division of Medical Oncology, Centro di Riferimento Tumori Rari Regione Campania, University of Naples “Federico II”, Napoli, Italy 3 The Institute of Cancer Research, Prostate Targeted Therapy Group, Sutton, UK 4 Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy Correspondence to: Giovannella Palmieri, email: giovpalm@unina.it Keywords: testicular cancer; vitamin D; testicular cancer survivors; long term side effects; quality of life Received: August 06, 2017 Accepted: December 05, 2017 Published: April 20, 2018 ABSTRACT Background: Cisplatin-based chemotherapy significantly improved the survival of patients with germ cell testicular cancer. However, long term side effects of chemotherapy have non-negligible impact on the quality of life of these young patients, who have a long life expectancy after being successfully treated. Materials and Methods: 25-OH vitamin D, testosterone, FSH and LH of patients with testicular cancer were retrospectively evaluated and for each patient clinical information were collected. The tissue of 52 patients with germ cell tumors was analyzed for VDR expression by immunohistochemistry. The serum 25-OH vitamin D and VDR expression were correlated to the patients ‘clinical characteristics. Results: 25-OH vitamin D was analyzed in 82 patients. Insufficient (< 30 ng/ml) levels were detected in 65%–85%, mild deficient (< 20 ng/ml) in 25%–36% and severe deficient (< 10 ng/ml) in 6%–18% of the patients over a median follow-up of 48 months. No difference in serum 25-OH vitamin D was detected over the follow-up time points. No correlation with histology, stage and type of treatment was found. The 25-OH vitamin D levels were not correlated to testosterone, FSH and LH levels. Interestingly, the expression of VDR was much higher in non seminoma than in seminoma tissue. Conclusions: Patients with testicular cancer have reduced vitamin D levels after the treatment of the primary cancer. Since long term hypovitaminosis D leads to high risk of fractures, infertility and cardiovascular diseases, we envision that vitamin D should be regularly checked in patients with testicular cancer and replaced if needed.
- Published
- 2018
68. Protein Expression of PTEN, Insulin-Like Growth Factor I Receptor (IGF-IR), and Lethal Prostate Cancer: A Prospective Study
- Author
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Kathryn L. Penney, Michelangelo Fiorentino, Meir J. Stampfer, Stephen P. Finn, Neil E. Martin, Richard Flavin, Lorelei A. Mucci, Massimo Loda, Ladan Fazli, Michael Pollak, Jennifer A. Sinnott, Jing Ma, Tarek A. Bismar, Edward Giovannucci, Rosina T. Lis, Martin E. Gleave, Ke Zu, Zu K, Martin NE, Fiorentino M, Flavin R, Lis RT, Sinnott JA, Finn S, Penney KL, Ma J, Fazli L, Gleave ME, Bismar TA, Stampfer MJ, Pollak MN, Loda M, Mucci LA, and Giovannucci E.
- Subjects
Oncology ,PCA3 ,medicine.medical_specialty ,biology ,Epidemiology ,business.industry ,Prostatectomy ,medicine.medical_treatment ,Prostate cancer, PTEN, IGF-IR ,medicine.disease ,Prostate cancer ,Antigen ,Internal medicine ,medicine ,biology.protein ,Immunohistochemistry ,PTEN ,business ,Prospective cohort study ,PI3K/AKT/mTOR pathway - Abstract
Background: Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality and the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway. Methods: Protein expression in tumor was evaluated using tumor tissues obtained from 805 participants of the Physicians' Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression and its interaction with IGF-IR, in relation to lethal prostate cancer (cancer-specific death or distant metastases). Results: Low PTEN expression was associated with an increased risk of lethal prostate cancer [HR, 1.7; 95% confidence interval (CI), 0.98–3.2; Ptrend = 0.04]. The association was attenuated after adjustment for Gleason grade, tumor stage, and prostate-specific antigen (PSA) at diagnosis. A significant negative interaction between PTEN and IGF-IR was found (Pinteraction = 0.03). Either reduction in PTEN or increase in IGF-IR expression was sufficient to worsen prognosis. Models including PTEN and IGF-IR expression offer additional predicting power to prostate cancer survival, compared to those only including demographic and clinical factors. Conclusions: Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF-IR expression remains at normal level. Impact: PTEN and IGF-IR expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(11); 1984–93. ©2013 AACR.
- Published
- 2013
69. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development
- Author
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Meritxell Gironella, Richard Tomasini, Julien Gommeaux, Yoshiharu Motoo, Martin E. Gleave, Min-Jue Xie, Marie-Josèphe Pébusque, Antonio Russo, Man Lung Yeung, Carla E. Cano, Mylène Seux, Stéphane Garcia, Ladan Fazli, Palma Rocchi, Juan L. Iovanna, Kuan-Teh Jeang, Amandine Chaix, Nelson Dusetti, Jonathan A. Nowak, Jean-Charles Dagorn, Alice Carrier, Qing Wang, GIRONELLA M, SEUX M, XIE MJ, CANO C, TOMASINI R, GOMMEAUX J, GARCIA S, NOWAK, YEUNG ML, JEANG KT, CHAIX A, FAZLI L, MOTOO Y, WANG Q, ROCCHI P, RUSSO A, GLEAVE M, DAGORN JC, IOVANNA JL, CARRIER A, PEBUSQUE MJ, and DUSETTI NJ
- Subjects
Settore MED/06 - Oncologia Medica ,Transplantation, Heterologous ,Gene Expression ,Mice, Nude ,Mice ,Pancreatic tumor ,Pancreatic cancer ,Cell Line, Tumor ,microRNA ,Gene expression ,medicine ,Animals ,Humans ,RNA, Neoplasm ,Nuclear protein ,Caspase ,Heat-Shock Proteins ,Mice, Knockout ,Multidisciplinary ,biology ,Base Sequence ,apoptosis, pancreatic cancer, ponasterone A, tumor suppressor, micro RNA ,Nuclear Proteins ,Biological Sciences ,medicine.disease ,Transplantation ,Pancreatic Neoplasms ,MicroRNAs ,Cell Transformation, Neoplastic ,Apoptosis ,Cancer research ,biology.protein ,Tumor Suppressor Protein p53 ,Carrier Proteins ,Neoplasm Transplantation ,Carcinoma, Pancreatic Ductal - Abstract
Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 ( TP53INP1 ) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1 −/− mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras V12 oncoproteins developed bigger tumors than TP53INP1 +/+ transformed MEFs or TP53INP1 −/− transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.
- Published
- 2007
70. Multi-scale relational graph convolutional network for multiple instance learning in histopathology images.
- Author
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Bazargani R, Fazli L, Gleave M, Goldenberg L, Bashashati A, and Salcudean S
- Subjects
- Humans, Male, Image Interpretation, Computer-Assisted methods, Image Processing, Computer-Assisted methods, Machine Learning, Algorithms, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Neural Networks, Computer
- Abstract
Graph convolutional neural networks have shown significant potential in natural and histopathology images. However, their use has only been studied in a single magnification or multi-magnification with either homogeneous graphs or only different node types. In order to leverage the multi-magnification information and improve message passing with graph convolutional networks, we handle different embedding spaces at each magnification by introducing the Multi-Scale Relational Graph Convolutional Network (MS-RGCN) as a multiple instance learning method. We model histopathology image patches and their relation with neighboring patches and patches at other scales (i.e., magnifications) as a graph. We define separate message-passing neural networks based on node and edge types to pass the information between different magnification embedding spaces. We experiment on prostate cancer histopathology images to predict the grade groups based on the extracted features from patches. We also compare our MS-RGCN with multiple state-of-the-art methods with evaluations on several source and held-out datasets. Our method outperforms the state-of-the-art on all of the datasets and image types consisting of tissue microarrays, whole-mount slide regions, and whole-slide images. Through an ablation study, we test and show the value of the pertinent design features of the MS-RGCN., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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71. Author Correction: IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling.
- Author
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Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, Greene S, Zeng Q, Fazli L, Rennie PS, Mills IG, Danielsen H, Theis F, Patterson JB, Jin Y, and Saatcioglu F
- Published
- 2024
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72. Prostate Cancer Risk Stratification by Digital Histopathology and Deep Learning.
- Author
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Shao Y, Bazargani R, Karimi D, Wang J, Fazli L, Goldenberg SL, Gleave ME, Black PC, Bashashati A, and Salcudean S
- Subjects
- Humans, Male, Risk Assessment methods, Prostatectomy methods, Aged, Middle Aged, Image Processing, Computer-Assisted methods, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Deep Learning, Neoplasm Grading
- Abstract
Purpose: Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current models are based on various clinical and pathologic parameters including Gleason grading, which suffers from a high interobserver variability. In this study, we determine whether objective machine learning (ML)-driven histopathology image analysis would aid us in better risk stratification of PCa., Materials and Methods: We propose a deep learning, histopathology image-based risk stratification model that combines clinicopathologic data along with hematoxylin and eosin- and Ki-67-stained histopathology images. We train and test our model, using a five-fold cross-validation strategy, on a data set from 502 treatment-naïve PCa patients who underwent radical prostatectomy (RP) between 2000 and 2012., Results: We used the concordance index as a measure to evaluate the performance of various risk stratification models. Our risk stratification model on the basis of convolutional neural networks demonstrated superior performance compared with Gleason grading and the Cancer of the Prostate Risk Assessment Post-Surgical risk stratification models. Using our model, 3.9% of the low-risk patients were correctly reclassified to be high-risk and 21.3% of the high-risk patients were correctly reclassified as low-risk., Conclusion: These findings highlight the importance of ML as an objective tool for histopathology image assessment and patient risk stratification. With further validation on large cohorts, the digital pathology risk classification we propose may be helpful in guiding administration of adjuvant therapy including radiotherapy after RP.
- Published
- 2024
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73. PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression.
- Author
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Li Y, Lv L, Ye M, Xie N, Fazli L, Wang Y, Wang W, Yang S, Ni Q, Chen J, Guo X, Zhao Y, Xue G, Sha J, Dong X, and Zhang L
- Subjects
- Animals, Humans, Male, Mice, Androgen Antagonists pharmacology, Androgen Antagonists adverse effects, Cell Line, Tumor, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Receptors, Androgen metabolism, Receptors, Androgen genetics, Thromboplastin metabolism, Thromboplastin genetics, Xenograft Model Antitumor Assays, Disease Progression, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Protein Disulfide-Isomerases metabolism, Protein Disulfide-Isomerases genetics, Venous Thrombosis metabolism, Venous Thrombosis chemically induced, Venous Thrombosis pathology, Venous Thrombosis genetics, Venous Thrombosis etiology
- Abstract
Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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74. Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression.
- Author
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Ma T, Jin L, Bai S, Liu Z, Wang S, Shen B, Cho Y, Cao S, Sun MJS, Fazli L, Zhang D, Wedderburn C, Zhang DY, Mugon G, Ungerleider N, Baddoo M, Zhang K, Schiavone LH, Burkhardt BR, Fan J, You Z, Flemington EK, Dong X, and Dong Y
- Subjects
- Male, Humans, Feedback, Transcriptome, Oncogene Proteins, Fusion genetics, Transcriptional Regulator ERG genetics, Transcriptional Regulator ERG metabolism, Neoplasm Proteins genetics, Cytokines genetics, Receptors, Androgen genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism
- Abstract
Background: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression., Methods: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome., Results: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling., Conclusion: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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75. A novel type-2 innate lymphoid cell-based immunotherapy for cancer.
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Saranchova I, Xia CW, Besoiu S, Finkel PL, Ellis SLS, Kari S, Munro L, Pfeifer CG, Fazli L, Gleave ME, and Jefferies WA
- Subjects
- Male, Humans, Mice, Animals, Cytokines, Interleukin-33, Lymphocytes, Immunity, Innate, Neoplasms therapy
- Abstract
Cell-based cancer immunotherapy has achieved significant advancements, providing a source of hope for cancer patients. Notwithstanding the considerable progress in cell-based immunotherapy, the persistently low response rates and the exorbitant costs associated with their implementation still present a formidable challenge in clinical settings. In the landscape of cell-based cancer immunotherapies, an uncharted territory involves Type 2 innate lymphoid cells (ILC2s) and interleukin-33 (IL-33) which promotes ILC2 functionality, recognized for their inherent ability to enhance immune responses. Recent discoveries regarding their role in actuating cytolytic T lymphocyte responses, including curbing tumor growth rates and hindering metastasis, have added a new dimension to our understanding of the IL-33/ILC2 axis. These recent insights may hold significant promise for ILC2 cell-based immunotherapy. Nevertheless, the prospect of adoptively transferring ILC2s to confer immune protection against tumors has yet to be investigated. The present study addresses this hypothesis, revealing that ILC2s isolated from the lungs of tumor-bearing mice, and tumor infiltrating ILC2s when adoptively transferred after tumor establishment at a ratio of one ILC2 per sixty tumor cells, leads to an influx of tumor infiltrating CD4+ and CD8+ T lymphocytes as well as tumor infiltrating eosinophils resulting in a remarkable reduction in tumor growth. Moreover, we find that post-adoptive transfer of ILC2s, the number of tumor infiltrating ILC2s is inversely proportional to tumor size. Finally, we find corollaries of the IL-33/ILC2 axis enhancing the infiltration of eosinophils in human prostate carcinomas patients' expressing high levels of IL-33 versus those expressing low levels of IL-33. Our results underscore the heightened efficacy of adoptively transferred ILC2s compared to alternative approaches, revealing an approximately one hundred fifty-fold superiority on a cell-per-cell basis over CAR T-cells in the specific targeting and elimination of tumors within the same experimental model. Overall, this study demonstrates the functional significance of ILC2s in cancer immunosurveillance and provides the proof of concept of the potential utility of ILC2 cell-based cancer immunotherapies., Competing Interests: WAJ is a founder and SLSE, LLN, SD, IS, KBC, CGP, PC, RJA and WAJ are equity holders in CaVa Healthcare Inc, the holder of UBC licenses and patents related to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Saranchova, Xia, Besoiu, Finkel, Ellis, Kari, Munro, Pfeifer, Fazli, Gleave and Jefferies.)
- Published
- 2024
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76. DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2.
- Author
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Kaarijärvi R, Kaljunen H, Nappi L, Fazli L, Kung SHY, Hartikainen JM, Paakinaho V, Capra J, Rilla K, Malinen M, Mäkinen PI, Ylä-Herttuala S, Zoubeidi A, Wang Y, Gleave ME, Hiltunen M, and Ketola K
- Subjects
- Male, Humans, Androgen Antagonists, Prostate pathology, Hydrolases, Microtubule-Associated Proteins, Enhancer of Zeste Homolog 2 Protein genetics, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism
- Abstract
Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a neuron-like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine-related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 decreases proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype, and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a driver of t-NEPC progression., (© 2024. The Author(s).)
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- 2024
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77. Molecular features of prostate cancer after neoadjuvant therapy in the phase 3 CALGB 90203 trial.
- Author
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Sumiyoshi T, Wang X, Warner EW, Sboner A, Annala M, Sigouros M, Beja K, Mizuno K, Ku S, Fazli L, Eastham J, Taplin ME, Simko J, Halabi S, Morris MJ, Gleave ME, Wyatt AW, and Beltran H
- Subjects
- Male, Humans, Neoadjuvant Therapy, Docetaxel, Androgen Antagonists therapeutic use, Androgens therapeutic use, Treatment Outcome, Neoplasm Recurrence, Local surgery, Prostate-Specific Antigen, Prostatectomy, Nuclear Proteins, Repressor Proteins, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms surgery
- Abstract
Background: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy., Methods: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes., Results: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes., Conclusions: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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78. RNF185 Control of COL3A1 Expression Limits Prostate Cancer Migration and Metastatic Potential.
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Van Espen B, Oo HZ, Collins C, Fazli L, Molinolo A, Yip K, Murad R, Gleave M, and Ronai ZA
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- Male, Humans, Mice, Animals, Prostate pathology, Cell Movement genetics, Epithelial-Mesenchymal Transition, RNA, Small Interfering, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Collagen Type III genetics, Collagen Type III metabolism, Mitochondrial Proteins genetics, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Prostatic Neoplasms pathology
- Abstract
RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER-associated degradation. Prostate tumor patient data analysis revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells stably expressing short hairpin RNA against RNF185 into mice resulted in larger tumors and more frequent lung metastases. RNA-sequencing and Ingenuity Pathway Analysis identified wound-healing and cellular movement among the most significant pathways upregulated in RNF185-depleted lines, compared with control prostate cancer cells. Gene Set Enrichment Analyses performed in samples from patients harboring low RNF185 expression and in RNF185-depleted lines confirmed the deregulation of genes implicated in epithelial-to-mesenchymal transition. Among those, COL3A1 was identified as the primary mediator of RNF185's ability to impact migration phenotypes. Correspondingly, enhanced migration and metastasis of RNF185 knockdown (KD) prostate cancer cells were attenuated upon co-inhibition of COL3A1. Our results identify RNF185 as a gatekeeper of prostate cancer metastasis, partly via its control of COL3A1 availability., Implications: RNF185 is identified as an important regulator of prostate cancer migration and metastasis, in part due to its regulation of COL3A1. Both RNF185 and COL3A1 may serve as novel markers for prostate tumors., (©2023 American Association for Cancer Research.)
- Published
- 2024
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79. Semaphorin 3C promotes de novo steroidogenesis in prostate cancer cells.
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Yenki P, Bhasin S, Liu L, Nabavi N, Cheng CW, Tam KJ, Peacock JW, Adomat HH, Tombe T, Fazli L, Ivanova L, Dusek C, Khosravi S, Guns EST, Wang Y, Buttyan R, Gleave ME, and Ong CJ
- Subjects
- Male, Humans, Androgens metabolism, Androgen Antagonists, Receptors, Androgen metabolism, Cholesterol metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms, Castration-Resistant metabolism, Semaphorins genetics, Semaphorins metabolism
- Abstract
Intratumoral androgen biosynthesis contributes to castration-resistant prostate cancer progression in patients treated with androgen deprivation therapy. The molecular mechanisms by which castration-resistant prostate cancer acquires the capacity for androgen biosynthesis to bypass androgen deprivation therapy are not entirely known. Here, we show that semaphorin 3C, a secreted signaling protein that is highly expressed in castration-resistant prostate cancer, can promote steroidogenesis by altering the expression profile of key steroidogenic enzymes. Semaphorin 3C not only upregulates enzymes required for androgen synthesis from dehydroepiandrosterone or de novo from cholesterol but also simultaneously downregulates enzymes involved in the androgen inactivation pathway. These changes in gene expression correlate with increased production of androgens induced by semaphorin 3C in prostate cancer model cells. Moreover, semaphorin 3C upregulates androgen synthesis in LNCaP cell-derived xenograft tumors, likely contributing to the enhanced in vivo tumor growth rate post castration. Furthermore, semaphorin 3C activates sterol regulatory element-binding protein, a transcription factor that upregulates enzymes involved in the synthesis of cholesterol, a sole precursor for de novo steroidogenesis. The ability of semaphorin 3C to promote intratumoral androgen synthesis may be a key mechanism contributing to the reactivation of the androgen receptor pathway in castration-resistant prostate cancer, conferring continued growth under androgen deprivation therapy. These findings identify semaphorin 3C as a potential therapeutic target for suppressing intratumoral steroidogenesis.
- Published
- 2023
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80. Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: A Multicenter Retrospective Study.
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Patel P, Harmon S, Iseman R, Ludkowski O, Auman H, Hawley S, Newcomb LF, Lin DW, Nelson PS, Feng Z, Boyer HD, Tretiakova MS, True LD, Vakar-Lopez F, Carroll PR, Cooperberg MR, Chan E, Simko J, Fazli L, Gleave M, Hurtado-Coll A, Thompson IM, Troyer D, McKenney JK, Wei W, Choyke PL, Bratslavsky G, Turkbey B, Siemens DR, Squire J, Peng YP, Brooks JD, and Jamaspishvili T
- Abstract
Phosphatase and tensin homolog (PTEN) loss is associated with adverse outcomes in prostate cancer and can be measured via immunohistochemistry. The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Postsurgical tissue microarray sections from the Canary Foundation (n = 1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by the pathologist and quantification of PTEN loss by AI (high-risk AI-qPTEN) were significantly associated with shorter metastasis-free survival (MFS) in univariable analysis (cPTEN hazard ratio [HR], 1.54; CI, 1.07-2.21; P = .019; AI-qPTEN HR, 2.55; CI, 1.83-3.56; P < .001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter MFS (HR, 2.17; CI, 1.49-3.17; P < .001) and recurrence-free survival (HR, 1.36; CI, 1.06-1.75; P = .016) when adjusting for relevant postsurgical clinical nomogram (Cancer of the Prostate Risk Assessment [CAPRA] postsurgical score [CAPRA-S]), whereas cPTEN does not show a statistically significant association (HR, 1.33; CI, 0.89-2; P = .2 and HR, 1.26; CI, 0.99-1.62; P = .063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR, 2.72; CI, 1.46-5.06; P = .002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy postsurgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding the AI-qPTEN assessment workflow to clinical variables may affect postoperative surveillance or management options, particularly in low-risk patients., (Copyright © 2023 United States & Canadian Academy of Pathology. All rights reserved.)
- Published
- 2023
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81. RNF185 control of COL3A1 expression limits prostate cancer migration and metastatic potential.
- Author
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Van Espen B, Oo HZ, Collins C, Fazli L, Molinolo A, Murad R, Gleave M, and Ronai ZA
- Abstract
RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER-associated degradation. Prostate tumor patient data analysis revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells stably expressing shRNA against RNF185 into mice resulted in larger tumors and more frequent lung metastases. RNA-sequencing and Ingenuity Pathway Analysis identified wound healing and cellular movement among the most significant pathways upregulated in RNF185-depleted, compared to control prostate cancer cells. Gene Set Enrichment Analyses performed in samples from patients harboring low RNF185 expression and in RNF185-depleted lines confirmed the deregulation of genes implicated in EMT. Among those, COL3A1 was identified as the primary mediator of RNF185's ability to impact migration phenotypes. Correspondingly, enhanced migration and metastasis of RNF185 KD prostate cancer cells were attenuated upon co-inhibition of COL3A1. Our results identify RNF185 as a gatekeeper of prostate cancer metastasis, partly via its control of COL3A1 availability.
- Published
- 2023
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82. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer.
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Jeon HY, Pornour M, Ryu H, Khadka S, Xu R, Jang J, Li D, Chen H, Hussain A, Fazli L, Gleave M, Dong X, Huang F, Wang Q, Barbieri C, and Qi J
- Subjects
- Humans, Male, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Prostate metabolism, Receptors, Androgen metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Smad3 Protein genetics, Smad3 Protein metabolism
- Abstract
Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ∼50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate cancer., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2023
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83. Chaperone-mediated autophagy promotes PCa survival during ARPI through selective proteome remodeling.
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Nikesitch N, Beraldi E, Zhang F, Adomat H, Bell R, Suzuki K, Fazli L, Hy Kung S, Wells C, Pinette N, Saxena N, Wang Y, and Gleave M
- Subjects
- Male, Humans, Receptors, Androgen genetics, Androgens metabolism, Proteome, Proteomics, Autophagy, Cell Line, Tumor, Prostatic Neoplasms, Castration-Resistant pathology, Chaperone-Mediated Autophagy
- Abstract
The androgen receptor (AR) plays an important role in PCa metabolism, with androgen receptor pathway inhibition (ARPI) subjecting PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. Defining acute stress response mechanisms that alleviate ARPI stress and therefore mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with ARPI. We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC); previously undefined in PCa. CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. Through selective protein degradation, CMA orchestrates the cellular stress response by regulating cellular pathways through selective proteome remodeling. Through broad-spectrum proteomic analysis, CMA coordinates metabolic reprogramming of PCa cells to sustain PCa growth and survival during ARPI; through the upregulation of mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. This not only promoted PCa growth during ARPI, but also promoted the emergence of CRPC in-vivo. During CMA inhibition, PCa metabolism is compromised, leading to ATP depletion, resulting in a profound anti-proliferative effect on PCa cells, and is enhanced when combined with ARPI. Furthermore, CMA inhibition prevented in-vivo tumour formation, and also re-sensitized enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. In summary, CMA is an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress, essential for ensuring PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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84. DDX5 mRNA-targeting antisense oligonucleotide as a new promising therapeutic in combating castration-resistant prostate cancer.
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Le TK, Cherif C, Omabe K, Paris C, Lannes F, Audebert S, Baudelet E, Hamimed M, Barbolosi D, Finetti P, Bastide C, Fazli L, Gleave M, Bertucci F, Taïeb D, and Rocchi P
- Subjects
- Male, Humans, RNA, Messenger therapeutic use, HSP27 Heat-Shock Proteins genetics, HSP27 Heat-Shock Proteins metabolism, HSP27 Heat-Shock Proteins therapeutic use, Cell Line, Tumor, DEAD-box RNA Helicases genetics, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense therapeutic use, Oligonucleotides, Antisense pharmacology, Prostatic Neoplasms, Castration-Resistant therapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
The heat shock protein 27 (Hsp27) has emerged as a principal factor of the castration-resistant prostate cancer (CRPC) progression. Also, an antisense oligonucleotide (ASO) against Hsp27 (OGX-427 or apatorsen) has been assessed in different clinical trials. Here, we illustrate that Hsp27 highly regulates the expression of the human DEAD-box protein 5 (DDX5), and we define DDX5 as a novel therapeutic target for CRPC treatment. DDX5 overexpression is strongly correlated with aggressive tumor features, notably with CRPC. DDX5 downregulation using a specific ASO-based inhibitor that acts on DDX5 mRNAs inhibits cell proliferation in preclinical models, and it particularly restores the treatment sensitivity of CRPC. Interestingly, through the identification and analysis of DDX5 protein interaction networks, we have identified some specific functions of DDX5 in CRPC that could contribute actively to tumor progression and therapeutic resistance. We first present the interactions of DDX5 and the Ku70/80 heterodimer and the transcription factor IIH, thereby uncovering DDX5 roles in different DNA repair pathways. Collectively, our study highlights critical functions of DDX5 contributing to CRPC progression and provides preclinical proof of concept that a combination of ASO-directed DDX5 inhibition with a DNA damage-inducing therapy can serve as a highly potential novel strategy to treat CRPC., Competing Interests: Declaration of interests The authors declare to have no financial, personal, or professional competing interest and no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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85. UGT2B28 accelerates prostate cancer progression through stabilization of the endocytic adaptor protein HIP1 regulating AR and EGFR pathways.
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Lacombe L, Hovington H, Brisson H, Mehdi S, Beillevaire D, Émond JP, Wagner A, Villeneuve L, Simonyan D, Ouellet V, Barrès V, Latour M, Aprikian A, Bergeron A, Castonguay V, Couture F, Chevalier S, Brimo F, Fazli L, Fleshner N, Gleave M, Karakiewicz PI, Lattouf JB, Trudel D, van der Kwast T, Mes-Masson AM, Pouliot F, Fradet Y, Audet-Walsh E, Saad F, Guillemette C, and Lévesque E
- Subjects
- Male, Humans, Prostate pathology, ErbB Receptors metabolism, Cell Line, Tumor, Canada, DNA-Binding Proteins genetics, Receptors, Androgen genetics, Receptors, Androgen metabolism, Prostatic Neoplasms pathology
- Abstract
The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2023
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86. CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.
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Tsujino T, Takai T, Hinohara K, Gui F, Tsutsumi T, Bai X, Miao C, Feng C, Gui B, Sztupinszki Z, Simoneau A, Xie N, Fazli L, Dong X, Azuma H, Choudhury AD, Mouw KW, Szallasi Z, Zou L, Kibel AS, and Jia L
- Subjects
- Humans, Male, BRCA1 Protein metabolism, DNA Repair genetics, Genes, BRCA2, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Drug Resistance, Neoplasm, Antineoplastic Agents pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics
- Abstract
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer., (© 2023. The Author(s).)
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- 2023
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87. Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression.
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Zhang F, Biswas M, Massah S, Lee J, Lingadahalli S, Wong S, Wells C, Foo J, Khan N, Morin H, Saxena N, Kung SHY, Sun B, Parra Nuñez AK, Sanchez C, Chan N, Ung L, Altıntaş UB, Bui JM, Wang Y, Fazli L, Oo HZ, Rennie PS, Lack NA, Cherkasov A, Gleave ME, Gsponer J, and Lallous N
- Subjects
- Male, Humans, Androgens, Transcription Factors metabolism, Gene Expression Regulation, Gene Expression, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Receptors, Androgen genetics, Receptors, Androgen metabolism, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism
- Abstract
Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2023
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88. TP53 Alterations Are Associated With Poor Survival in Patients With Primary Mediastinal Nonseminoma Germ Cell Tumors.
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Bacon JVW, Giannatempo P, Cataldo G, Fazli L, Saxena N, Ozgun G, Soleimani M, Chi K, Nichols C, Necchi A, Wyatt AW, Kollmannsberger CK, and Nappi L
- Subjects
- Male, Humans, Prognosis, Tumor Suppressor Protein p53 genetics, Neoplasms, Germ Cell and Embryonal genetics, Testicular Neoplasms genetics, Testicular Neoplasms pathology, Seminoma pathology, Mediastinal Neoplasms genetics, Mediastinal Neoplasms pathology
- Abstract
Background: Primary mediastinal nonseminoma germ cell tumors (PMNSGCT) are a subgroup of nonseminoma germ cell tumors (GCT) with poor prognosis. In this study, PMNSGCT-specific genomic landscape was analyzed and correlated with clinical outcomes., Methods: DNA was extracted and sequenced from 28 archival tumor tissue of patients with mediastinal GCT (3 seminoma and 25 nonseminoma). Overall survival (OS) and association with gene alterations were estimated using the Kaplan-Meier and univariate Cox regression methods., Results: Three patients (11%) had a karyotype XXY, 17/28 (61%) tumor samples presented chromosome 12p amplification. Somatic mutations were detected in 19/28 (68%) samples. The most frequently mutated genes were: TP53 (13/28; 46%), KIT (5/28; 18%), and KRAS (5/28; 18%). Deleterious TP53 alterations were associated with significantly reduced overall survival (HR: 7.16; P = .012)., Conclusions: TP53 alterations are common in PMNSGCT and are associated with reduced overall survival, potentially underlying the poor sensitivity to chemotherapy observed in these patients., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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89. Robust Nanoparticle-Derived Lubricious Antibiofilm Coating for Difficult-to-Coat Medical Devices with Intricate Geometry.
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Yazdani-Ahmadabadi H, Yu K, Khoddami S, F Felix D, Yeh HH, Luo HD, Moskalev I, Wang Q, Wang R, Grecov D, Fazli L, Lange D, and Kizhakkedathu JN
- Abstract
A major medical device-associated complication is the biofilm-related infection post-implantation. One promising approach to prevent this is to coat already commercialized medical devices with effective antibiofilm materials. However, developing a robust high-performance antibiofilm coating on devices with a nonflat geometry remains unmet. Here, we report the development of a facile scalable nanoparticle-based antibiofilm silver composite coating with long-term activity applicable to virtually any objects including difficult-to-coat commercially available medical devices utilizing a catecholic organic-aqueous mixture. Using a screening approach, we have identified a combination of the organic-aqueous buffer mixture which alters polycatecholamine synthesis, nanoparticle formation, and stabilization, resulting in controlled deposition of in situ formed composite silver nanoparticles in the presence of an ultra-high-molecular-weight hydrophilic polymer on diverse objects irrespective of its geometry and chemistry. Methanol-mediated synthesis of polymer-silver composite nanoparticles resulted in a biocompatible lubricious coating with high mechanical durability, long-term silver release (∼90 days), complete inhibition of bacterial adhesion, and excellent killing activity against a diverse range of bacteria over the long term. Coated catheters retained their excellent activity even after exposure to harsh mechanical challenges (rubbing, twisting, and stretching) and storage conditions (>3 months stirring in water). We confirmed its excellent bacteria-killing efficacy (>99.999%) against difficult-to-kill bacteria ( Proteus mirabilis ) and high biocompatibility using percutaneous catheter infection mice and subcutaneous implant rat models, respectively, in vivo . The developed coating approach opens a new avenue to transform clinically used medical devices (e.g., urinary catheters) to highly infection-resistant devices to prevent and treat implant/device-associated infections., Competing Interests: The authors declare the following competing financial interest(s): The University of British Columbia has filed a patent application based on the research described with H.Y.A., K.Y., D.L., and J.N.K. as inventors., (© 2022 The Authors. Published by American Chemical Society.)
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- 2022
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90. Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer.
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Al-Nakouzi N, Wang CK, Oo HZ, Nelepcu I, Lallous N, Spliid CB, Khazamipour N, Lo J, Truong S, Collins C, Hui D, Esfandnia S, Adomat H, Clausen TM, Gustavsson T, Choudhary S, Dagil R, Corey E, Wang Y, Chauchereau A, Fazli L, Esko JD, Salanti A, Nelson PS, Gleave ME, and Daugaard M
- Subjects
- Androgens, Chondroitin Sulfates, Glycocalyx metabolism, Humans, Male, Signal Transduction, Tumor Microenvironment, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer., (© 2022. The Author(s).)
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- 2022
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91. Analysis of separate training and validation radical prostatectomy cohorts identifies 0.25 mm diameter as an optimal definition for "large" cribriform prostatic adenocarcinoma.
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Chan E, McKenney JK, Hawley S, Corrigan D, Auman H, Newcomb LF, Boyer HD, Carroll PR, Cooperberg MR, Klein E, Fazli L, Gleave ME, Hurtado-Coll A, Simko JP, Nelson PS, Thompson IM, Tretiakova MS, Troyer D, True LD, Vakar-Lopez F, Lin DW, Brooks JD, Feng Z, and Nguyen JK
- Subjects
- Humans, Male, Neoplasm Grading, Prostatectomy, Retrospective Studies, Adenocarcinoma pathology, Prostatic Neoplasms pathology
- Abstract
Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p < 0.001). In addition, two different subset analyses of low-intermediate risk cases (cases with Gleason score ≤ 3 + 4 = 7; and cases with Gleason score = 3 + 4 = 7/4 + 3 = 7) likewise demonstrated patients with largest cribriform diameter >0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma., (© 2022. The Author(s).)
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- 2022
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92. The different prognostic significance of polysialic acid and CD56 expression in tumor cells and lymphocytes identified in breast cancer.
- Author
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Soukhtehzari S, Berish RB, Fazli L, Watson PH, and Williams KC
- Abstract
Protein glycosylation, the attachment of carbohydrates onto proteins, is a fundamental process that alters the biological activity of proteins. Changes to glycosylation states are associated with many forms of cancer including breast cancer. Through immunohistological analysis of breast cancer patient tumors, we have discovered the expression of an atypical glycan-polysialic acid (polySia)-in breast cancer. Notably, we have identified polySia expression in not only tumor cells but also on tumor-infiltrating lymphocytes (TILs) and our study reveals ST8Sia4 as the predominant polysialyltransferase expressed. Evaluation of ST8Sia4 expression in tumor cells identified an association between high expression levels and poor patient outcomes whereas ST8Sia4 expression in infiltrating stromal cells was associated with good patient outcomes. Investigation into CD56, a protein known to be polysialylated, found CD56 and polySia expression on breast tumor cells and TILs. CD56 expression did not positively correlate with polySia expression except in patient tumors which expressed HER2. In these HER2 expressing tumors, CD56 expression was significantly associated with HER2 expression score. Evaluation of CD56 tumor cell expression identified a significant association between CD56 expression and poor patient outcomes. By contrast, CD56 expression on TILs was significantly associated with good clinical outcomes. Tumors with CD56+ TILs were also consistently polySia TIL positive. Interestingly, in tumors where TILs were CD56 low-to-negative, a polySia+ lymphocyte population was still identified and the presence of these lymphocytes was a poor prognostic indicator. Overall, this study provides the first detailed report of polySia and CD56 in breast cancer and demonstrates that the prognostic significance is dependent on the cell type expression within the tumor., (© 2022. The Author(s).)
- Published
- 2022
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93. Durable Surfaces from Film-Forming Silver Assemblies for Long-Term Zero Bacterial Adhesion without Toxicity.
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Yazdani-Ahmadabadi H, Felix DF, Yu K, Yeh HH, Luo HD, Khoddami S, Takeuchi LE, Alzahrani A, Abbina S, Mei Y, Fazli L, Grecov D, Lange D, and Kizhakkedathu JN
- Abstract
The long-term prevention of biofilm formation on the surface of indwelling medical devices remains a challenge. Silver has been reutilized in recent years for combating biofilm formation due to its indisputable bactericidal potency; however, the toxicity, low stability, and short-term activity of the current silver coatings have limited their use. Here, we report the development of silver-based film-forming antibacterial engineered (SAFE) assemblies for the generation of durable lubricous antibiofilm surface long-term activity without silver toxicity that was applicable to diverse materials via a highly scalable dip/spray/solution-skinning process. The SAFE coating was obtained through a large-scale screening, resulting in effective incorporation of silver nanoparticles (∼10 nm) into a stable nonsticky coating with high surface hierarchy and coverage, which guaranteed sustained silver release. The lead coating showed zero bacterial adhesion over a 1 month experiment in the presence of a high load of diverse bacteria, including difficult-to-kill and stone-forming strains. The SAFE coating showed high biocompatibility and excellent antibiofilm activity in vivo ., Competing Interests: The authors declare the following competing financial interest(s): The University of British Columbia has filed for patent protection on the technology described here. H.Y.-A., K.Y., D.L., and J.N.K. are named as inventors on a PCT patent application submitted. The rest of the authors declare no competing interests., (© 2022 The Authors. Published by American Chemical Society.)
- Published
- 2022
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94. Receptor Activator of NF Kappa B (RANK) Expression Indicates Favorable Prognosis in Patients with Muscle-invasive Bladder Cancer.
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Maas M, Rausch S, Guttenberg T, Seiler R, Hennenlotter J, Oo HZ, Fazli L, Kühs U, Gakis G, Stenzl A, Schwentner C, Black PC, and Todenhöfer T
- Subjects
- Humans, Lymphatic Metastasis, Muscles metabolism, Muscles pathology, Prognosis, Receptor Activator of Nuclear Factor-kappa B metabolism, Urinary Bladder Neoplasms pathology
- Abstract
Background: Receptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown., Objective: To assess the relevance of RANK expression in patients with MIBC., Design, Setting, and Participants: Expression of RANK was assessed via immunohistochemistry of benign urothelium, MIBC tissue, and lymph node metastases from 153 patients undergoing radical cystectomy. Expression data from The Cancer Genome Atlas (TCGA) cohort were analyzed for potential associations with molecular subtypes and outcome., Outcome Measurements and Statistical Analysis: RANK expression was correlated with clinical and pathological parameters and to individual data for the clinical course of MIBC., Results and Limitations: Expression of RANK was significantly higher in both primary tumors (p = 0.02) and lymph node metastases (p = 0.01) compared to normal urothelium. In tumor tissue, RANK expression was significantly lower in patients with locally advanced disease and lymph node involvement compared to those with organ-confined disease (p = 0.0009) and node-negative MIBC (p = 0.0002). In univariable and multivariable analyses, high expression of RANK was associated with a longer time to recurrence (p = 0.0005 and 0.01) and better cancer-specific (p = 0.0004 and 0.007) and overall survival (p = 0.002 and 0.04). High expression of RANK was associated with better outcome for patients with luminal infiltrated tumors in the TCGA cohort., Conclusions: RANK expression is increased in bladder cancer tissue compared to benign urothelium, with higher expression in organ-defined compared to locally advanced disease. High RANK expression indicates a favorable prognosis in MIBC. The prognostic role differs in tumors of different molecular subtypes., Patient Summary: Expression of a protein involved in bone turnover regulation (RANK) is higher in bladder cancer tissue than in benign bladder tissue. However, high levels of RANK on tumor cells indicate favorable prognosis for patients with bladder cancer that invades the muscle layer of the bladder., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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95. Development and validation of a quantitative reactive stroma biomarker (qRS) for prostate cancer prognosis.
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Ruder S, Gao Y, Ding Y, Bu P, Miles B, De Marzo A, Wheeler T, McKenney JK, Auman H, Fazli L, Simko J, Hurtado-Coll A, Troyer DA, Carroll PR, Gleave M, Platz E, Trock B, Han M, Sayeeduddin M, True LD, Rowley D, Lin DW, Nelson PS, Thompson IM, Feng Z, Wei W, Brooks JD, Ittmann M, Lee M, and Ayala G
- Subjects
- Biomarkers, Tumor analysis, Humans, Male, Neoplasm Recurrence, Local pathology, Prognosis, Prostate-Specific Antigen, Prostatectomy methods, Retrospective Studies, Prostate pathology, Prostate surgery, Prostatic Neoplasms pathology
- Abstract
To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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96. THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.
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Blomme A, Peter C, Mui E, Rodriguez Blanco G, An N, Mason LM, Jamieson LE, McGregor GH, Lilla S, Ntala C, Patel R, Thiry M, Kung SHY, Leclercq M, Ford CA, Rushworth LK, McGarry DJ, Mason S, Repiscak P, Nixon C, Salji MJ, Markert E, MacKay GM, Kamphorst JJ, Graham D, Faulds K, Fazli L, Gleave ME, Avezov E, Edwards J, Yin H, Sumpton D, Blyth K, Close P, Murphy DJ, Zanivan S, and Leung HY
- Subjects
- Gene Expression Regulation, Neoplastic, Humans, Lipid Metabolism, Male, Androgen Antagonists pharmacology, Androgen Antagonists therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2022
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97. Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer.
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Yi Y, Li Y, Li C, Wu L, Zhao D, Li F, Fazli L, Wang R, Wang L, Dong X, Zhao W, Chen K, and Cao Q
- Subjects
- Cell Cycle Proteins genetics, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Male, Methylation, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism
- Abstract
Cell division cycle-associated 8 (CDCA8) is a component of chromosomal passenger complex (CPC) that participates in mitotic regulation. Although cancer-related CDCA8 hyperactivation has been widely observed, its molecular mechanism remains elusive. Here, we report that CDCA8 overexpression maintains tumorigenicity and is associated with poor clinical outcome in patients with prostate cancer (PCa). Notably, enhancer of zeste homolog 2 (EZH2) is identified to be responsible for CDCA8 activation in PCa. Genome-wide assays revealed that EZH2-induced H3K27 trimethylation represses let-7b expression and thus protects the let-7b-targeting CDCA8 transcripts. More importantly, EZH2 facilitates the self-activation of E2F1 by recruiting E2F1 to its own promoter region in a methylation-independent manner. The high level of E2F1 further promotes transcription of CDCA8 along with the other CPC subunits. Taken together, our study suggests that EZH2-mediated cell cycle regulation in PCa relies on both its methyltransferase and non-methyltransferase activities., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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98. Regulation of AR mRNA translation in response to acute AR pathway inhibition.
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Somasekharan SP, Saxena N, Zhang F, Beraldi E, Huang JN, Gentle C, Fazli L, Thi M, Sorensen PH, and Gleave M
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- Cell Line, Tumor, Humans, Male, Protein Biosynthesis, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, RNA, Messenger metabolism, Receptors, Androgen genetics
- Abstract
We report a new mechanism of androgen receptor (AR) mRNA regulation and cytoprotection in response to AR pathway inhibition (ARPI) stress in prostate cancer (PCA). AR mRNA translation is coordinately regulated by RNA binding proteins, YTHDF3 and G3BP1. Under ambient conditions m6A-modified AR mRNA is bound by YTHDF3 and translationally stimulated, while m6A-unmodified AR mRNA is bound by G3BP1 and translationally repressed. When AR-regulated PCA cell lines are subjected to ARPI stress, m6A-modified AR mRNA is recruited from actively translating polysomes (PSs) to RNA-protein stress granules (SGs), leading to reduced AR mRNA translation. After ARPI stress, m6A-modified AR mRNA liquid-liquid phase separated with YTHDF3, while m6A-unmodified AR mRNA phase separated with G3BP1. Accordingly, these AR mRNA messages form two distinct YTHDF3-enriched or G3BP1-enriched clusters in SGs. ARPI-induced SG formation is cell-protective, which when blocked by YTHDF3 or G3BP1 silencing increases PCA cell death in response to ARPI stress. Interestingly, AR mRNA silencing also delays ARPI stress-induced SG formation, highlighting its supportive role in triggering this stress response. Our results define a new mechanism for stress adaptive cell survival after ARPI stress involving SG-regulated translation of AR mRNA, mediated by m6A RNA modification and their respective regulatory proteins., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2022
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99. Menin inhibition suppresses castration-resistant prostate cancer and enhances chemosensitivity.
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Cherif C, Nguyen DT, Paris C, Le TK, Sefiane T, Carbuccia N, Finetti P, Chaffanet M, Kaoutari AE, Vernerey J, Fazli L, Gleave M, Manai M, Barthélémy P, Birnbaum D, Bertucci F, Taïeb D, and Rocchi P
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Humans, Male, Prostatic Neoplasms, Castration-Resistant pathology, Genomics methods, Prostatic Neoplasms, Castration-Resistant genetics, Proto-Oncogene Proteins metabolism
- Abstract
Disease progression and therapeutic resistance of prostate cancer (PC) are linked to multiple molecular events that promote survival and plasticity. We previously showed that heat shock protein 27 (HSP27) acted as a driver of castration-resistant phenotype (CRPC) and developed an oligonucleotides antisense (ASO) against HSP27 with evidence of anti-cancer activity in men with CRPC. Here, we show that the tumor suppressor Menin (MEN1) is highly regulated by HSP27. Menin is overexpressed in high-grade PC and CRPC. High MEN1 mRNA expression is associated with decreased biochemical relapse-free and overall survival. Silencing Menin with ASO technology inhibits CRPC cell proliferation, tumor growth, and restores chemotherapeutic sensitivity. ChIP-seq analysis revealed differential DNA binding sites of Menin in various prostatic cells, suggesting a switch from tumor suppressor to oncogenic functions in CRPC. These data support the evaluation of ASO against Menin for CRPC., (© 2021. The Author(s).)
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- 2022
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100. High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics.
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Kesch C, Yirga L, Dendl K, Handke A, Darr C, Krafft U, Radtke JP, Tschirdewahn S, Szarvas T, Fazli L, Gleave M, Giesel FL, Haberkorn U, and Hadaschik B
- Subjects
- Androgen Antagonists, Fibroblasts, Humans, Male, Positron Emission Tomography Computed Tomography, Precision Medicine, Prostatic Neoplasms, Castration-Resistant diagnostic imaging
- Abstract
Purpose: To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [
68 Ga]Ga-FAPI-04 PET/CT imaging in patients with castration-resistant PC (CRPC)., Methods: Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [68 Ga]Ga-FAPI-04 PET/CT, and PET positivity was analyzed., Results: The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [68 Ga]Ga-FAPI-04 PET/CT was highly positive in men with advanced CRPC., Conclusion: Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC., (© 2021. The Author(s).)- Published
- 2021
- Full Text
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