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Prostate Cancer Reshapes the Secreted and Extracellular Vesicle Urinary Proteomes

ABSTRACT: Urine is a remarkably complex fluid, providing a non-invasive snapshot of an individual's overall physiologic state and of the genitourinary tissues through which it passes. Urine includes both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To better understand the population variability and clinical utility of urine, we comprehensively profiled both the secreted and EV proteomes of 190 men, including prostate cancer patients. We demonstrate a simple protocol to enrich for prostatic proteins in urine, and show that secreted and EV proteins reflect different subcellular compartments. Urinary proteomes are accurate surrogates of tissue proteomes, but proteins secreted from cell lines are not. The urinary proteome is longitudinally stable, and accurately distinguishes malignant from benign prostatic lesions, and can risk-stratify prostate tumors. Taken together, this resource quantifies the complexity of the urinary proteome, and reveals the synergistic value of distinguishing secreted and EV proteomes for biomarker studies.

INSTRUMENT(S): Orbitrap Fusion, Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Thomas Kislinger

PROVIDER: MSV000092061 | MassIVE | Wed May 31 07:42:00 BST 2023

REPOSITORIES: MassIVE

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Project description:Objectives: Secretion of extracellular vesicles (EV) and associated micro-RNAs (miR) is altered during cellular stress and may serve as biomarkers of organ injury. We hypothesized that measuring changes in urinary levels of EV and miR will predict the onset of acute kidney injury in cardiac surgery patients. Design: Predictive accuracy biomarker study performed in the cohort of the REVAKI-2 trial Setting: Single center ICU between September 2015 and September 2018 Interventions: Intravenous sildenafil citrate 12.5 mg kg-1 over 150 min or dextrose 5% at the commencement of surgery. Measurements and main results: Urine samples were collected before and 24 hours after the procedure from 93 cardiac surgery patients. Urine EV concentrations and size distribution were assessed using NanoSight. EV derivation and levels were measured using flow cytometry. Samples from 10 selected patients were sequenced to detect differentially expressed miR. Verification was performed with advanced TaqMan assays in samples from all patients. Urine EV concentrations significantly increased in patients with AKI after surgery, with the percentage of EV positive for aquaporin-2 and β1-integrin also increasing. Pre surgery podocalyxin-positive EV were significantly lower, and β1-integrin EV werehigher in patients with AKI. The levels of the former correlated with the severity of theinjury. miR-125a-5p was expressed at higher levels in urine from patients with AKI stage 2/3. Levels of miR-10a-5p decreased after surgery in AKI patients; its levels correlated with the severity of the injury. Preoperative levels of podocalyxin EVs and miR-125a-5p had moderate AKI predictive value and, in a logistic model together with ICU lactate levels, offered good (AUC = 80.9%) AKI prediction. Conclusions: Lower levels of podocalyxin-positive EV at baseline predict the severity of post-surgery AKI. Urine EV concentrations and miR expression offer excellent predictive accuracy when combined with commonly measured biomarkers.

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Prostate Cancer Reshapes the Secreted and Extracellular Vesicle Urinary Proteomes

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