标题：Multi-omics & pathway analysis identify potential roles for tumor N-acetyl aspartate accumulation in murine models of castration-resistant prostate cancer
摘要：SummaryCastration-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 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.Graphical abstractDisplay OmittedHighlights•Castration-resistant prostate cancer (CRPC) remains a major clinical challenge•Human prostate cancer cells grown as orthografts are useful pre-clinical CRPC models•Multi-omics analysis of hormone-responsive and resistant orthografts were performed•Altered tumoral N-acetyl aspartate and related pathway are implicated in CRPCCell biology; Proteomics; Metabolomics
