Multi-omics and Pathway Analysis Identify Potential Roles for Tumour N-Acetyl Aspartate Accumulation in Murine Models of Castration Resistant Prostate Cancer

Published: 8 March 2022| Version 1 | DOI: 10.17632/6jz2y44w4x.1
Mark Salji


Untargeted Metabolomics, Proteomics and RNA sequencing of three xenograft models of CRPC. Reactome pathways .gmt file used for pathway analysis is included. Summary: Castration-resistant prostate cancer (CRPC) is incurable and remains a significant worldwide challenge. 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.



Beatson Institute for Cancer Research, Glasgow Caledonian University


Prostate Cancer, Hormonal Treatment of Prostate Cancer