Multi-omics & pathway analysis identify potential roles for tumor N-acetyl aspartate accumulation in murine models of castration-resistant prostate cancer
Mark J. Salji,
Arnaud Blomme,
J. Henry M. Däbritz,
Peter Repiscak,
Sergio Lilla,
Rachana Patel,
David Sumpton,
Niels J.F. van den Broek,
Ronan Daly,
Sara Zanivan,
Hing Y. Leung
Affiliations
Mark J. Salji
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK; Corresponding author
Arnaud Blomme
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
J. Henry M. Däbritz
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Peter Repiscak
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Sergio Lilla
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Rachana Patel
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
David Sumpton
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Niels J.F. van den Broek
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Ronan Daly
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Sara Zanivan
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Hing Y. Leung
Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK; Corresponding author
Summary: 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 were performed on xenografts derived from three independent sets of hormone naive 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 hypothesize 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 tumor growth.
