Multi-omics and pathway analysis identify potential roles for tumour n-acetyl aspartate accumulation in murine models of castration resistant prostate cancer

Salji, M. J. et al. (2022) Multi-omics and pathway analysis identify potential roles for tumour n-acetyl aspartate accumulation in murine models of castration resistant prostate cancer. iScience, 25(4), 104056. (doi: 10.1016/j.isci.2022.104056) (PMID:35345457) (PMCID:PMC8957019)

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Abstract

Castration-resistant prostate cancer (CRPC) is incurable and remains a significant worldwide challenge (Oakes and Papa, 2015). Matched untargeted multi-level omic datasets may reveal biological changes driving CRPC, identifying novel biomarkers and/or therapeutic targets. Untargeted RNA sequencing, proteomics, and metabolomics was performed on xenografts derived from three independent sets of hormone naïve and matched CRPC human cell line models of local, lymph node and bone metastasis grown as murine orthografts. Collectively, we tested the feasibility of muti-omics analysis on models of CRPC in revealing pathways of interest for future validation investigation. Untargeted metabolomics revealed NAA and NAAG commonly accumulating in CRPC across three independent models and proteomics showed upregulation of related enzymes, namely N-Acetylated Alpha-Linked Acidic Dipeptidases (FOLH1/NAALADL2). Based on pathway analysis integrating multiple omic levels we hypothesise that increased NAA in CRPC may be due to upregulation of NAAG hydrolysis via NAALADLases providing a pool of Acetyl Co-A for upregulated sphingolipid metabolism and a pool of glutamate and aspartate for nucleotide synthesis during tumour growth.

Item Type:Articles
Additional Information:This work was supported by the Medical Research Council Clinical Research Training Fellowship awarded to MS (MR/L017997/1) and CRUK Beatson Institute core funding (C596/A31287) and CRUK core group awarded to HYL (A15151) and SZ (A29800).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lilla, Dr Sergio and Leung, Professor Hing and Zanivan, Professor Sara and Repiscak, Dr Peter and Däbritz, Jan and Van Den Broek, Mr Niels and Salji, Dr Mark and Sumpton, Mr David and Patel, Dr Rachana and Daly, Dr Ronan
Authors: Salji, M. J., Blomme, A., Däbritz, J. H. M., Repiscak, P., Lilla, S., Patel, R., Sumpton, D., Van Den Broek, N. J. F., Daly, R., Zanivan, S., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:iScience
Publisher:Elsevier (Cell Press)
ISSN:2589-0042
ISSN (Online):2589-0042
Published Online:11 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in iScience 25(4): 104056
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170128Quantitative proteomic analysis of castrate-resistant prostate cancerHing LeungMedical Research Council (MRC)MR/L017997/1Institute of Cancer Sciences