Abstract
Sensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed. Urine samples are a non-invasive means to obtain abundant and readily accessible “liquid biopsies”. Herein we used urine liquid biopsies to identify and characterize a novel group of urine-enriched RNAs and metabolites in patients with PCa and normal individuals with or without benign prostatic disease. Differentially expressed RNAs were identified in urine samples by deep sequencing and metabolites in urine were measured by mass spectrometry. mRNA and metabolite profiles were distinct in patients with benign and malignant disease. Integrated analysis of urinary gene expression and metabolite signatures unveiled an aberrant glutamate metabolism and tricarboxylic acid (TCA) cycle node in prostate cancer-derived cells. Functional validation supported a role for glutamate metabolism and glutamate oxaloacetate transaminase 1 (GOT1)-dependent redox balance in PCa, which could be exploited for novel biomarkers and therapies. In this study, we discovered cancer-specific changes in urinary RNAs and metabolites, paving the way for the development of sensitive and specific urinary PCa diagnostic biomarkers either alone or in combination. Our methodology was based on single void urine samples (i.e., without prostatic massage). The integrated analysis of metabolomic and transcriptomic data from these liquid biopsies revealed a glutamate metabolism and tricarboxylic acid cycle node that was specific to prostate-derived cancer cells and cancer-specific metabolic changes in urine.
Highlights
Sensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed
In this study we identified a group of RNA and metabolite signatures in urine as putative PCa biomarkers and therapeutic targets
To improve the accuracy of disease classification, we carried out metabolic and transcriptomic profiling of urine obtained from benign prostatic hyperplasia (BPH), PTT, and PCa patients
Summary
Sensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed. We used urine liquid biopsies to identify and characterize a novel group of urineenriched RNAs and metabolites in patients with PCa and normal individuals with or without benign prostatic disease. Integrated analysis of urinary gene expression and metabolite signatures unveiled an aberrant glutamate metabolism and tricarboxylic acid (TCA) cycle node in prostate cancer-derived cells. Prostate cancer antigen 3 (PCA3), a prostate-specific non-coding RNA, was approved by the FDA in 2012 as the first PCa molecular diagnostic test for a particular clinical indication (need for recurrence prostate biopsies in men aged >50 years with assumed PSA levels and/or DRE and/or one or more earlier negative biopsies)[5]. The utility of sarcosine as a biomarker is provocative and clinical validation has been indefinable[17]
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