Liquid Biopsy-Based Exo-oncomiRNAs Can Predict Prostate Cancer Aggressiveness

SIMPLE SUMMARY: The main problem encountered in the management of prostate cancer (PCa) is the inability to distinguish slow-growing indolent tumors from aggressive tumors. It is therefore important to explore non-invasive assays for the early detection of this aggressive subtype, when it can still be treated effectively. The presence of the TWEAK cytokine in biofluids of the PCa microenvironment might drive the secretion of extracellular vesicles (EVs) containing exo-oncomicroRNAs capable of modifying the tumor microenvironment. These exo-oncomicroRNAs are potentially useful as PCa biomarkers. We identified 2 exo-oncomiRNAs isolated from semen EVs by the action of TWEAK in the tumor microenvironment and, we determined their usefulness as biomarkers of PCa prognostic. We also established, for the first time, that TWEAK modulates potential exo-oncomiRNA targets, both tightly linked to cancer progression. In conclusion, our study shows that semen detection of TWEAK-regulated exo-oncomiRNAs can improve PCa prognosis, opening new avenues for diagnosis and treatment. ABSTRACT: Liquid biopsy-based biomarkers, including microRNAs packaged within extracellular vesicles, are promising tools for patient management. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is related to PCa progression and is found in the semen of patients with PCa. TWEAK can induce the transfer of exo-oncomiRNAs from tumor cells to body fluids, and this process might have utility in non-invasive PCa prognosis. We investigated TWEAK-regulated exo-microRNAs in semen and in post-digital rectal examination urine from patients with different degrees of PCa aggressiveness. We first identified 14 exo-oncomiRNAs regulated by TWEAK in PCa cells in vitro, and subsequently validated those using liquid biopsies from 97 patients with PCa. Exo-oncomiR-221-3p, -222-3p and -31-5p were significantly higher in the semen of high-risk patients than in low-risk peers, whereas exo-oncomiR-193-3p and -423-5p were significantly lower in paired samples of post-digital rectal examination urine. A panel of semen biomarkers comprising exo-oncomiR-221-3p, -222-3p and TWEAK was designed that could correctly classify 87.5% of patients with aggressive PCa, with 85.7% specificity and 76.9% sensitivity with an area under the curve of 0.857. We additionally found that TWEAK modulated two exo-oncomiR-221-3p targets, TCF12 and NLK. Overall, we show that liquid biopsy detection of TWEAK-regulated exo-oncomiRNAs can improve PCa prognosis prediction.