Multi-Omics Analysis Identifies Local N-Acetyl Aspartate Accumulation as a Feature of Castration Resistant Prostate Cancer

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 naive and matched CRPC human cell line models of local, lymph node and bone metastasis grown as murine orthografts. 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.