Urinary extracellular vesicles contain mature transcriptome enriched in circular and long noncoding RNAs with functional significance in prostate cancer

Abstract

Long noncoding (lnc)RNAs modulate gene expression alongside presenting unexpected source of neoantigens. Despite their immense interest, their ability to be transferred and control adjacent cells is unknown. Extracellular Vesicles (EVs) offer a protective environment for nucleic acids, with pro and antitumourigenic functions by controlling the immune response. In contrast to extracellular nonvesicular RNA, few studies have addressed the full RNA content within human fluids' EVs and have compared them with their tissue of origin. Here, we performed Total RNA-Sequencing on six Formalin-Fixed-Paraffin-Embedded (FFPE) prostate cancer (PCa) tumour tissues and their paired urinary (u)EVs to provide the first whole transcriptome comparison from the same patients. UEVs contain simplified transcriptome with intronfree cytoplasmic transcripts and enriched lnc/circular (circ)RNAs, strikingly common to an independent 20 patients' urinary cohort. Our full cellular and EVs transcriptome comparison within three PCa cell lines identified a set of overlapping 14 uEV-circRNAs characterized as essential for prostate cell proliferation in vitro and 28 uEV-lncRNAs belonging to the cancer-related lncRNA census (CLC2). In addition, we found 15 uEV-lncRNAs, predicted to encode 768 high-affinity neoantigens, and for which three of the encoded-ORF produced detectable unmodified peptidesThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

An in vitro approach to understand contribution of kidney cells to human urinary extracellular vesicles

“…However, at present it is not yet clear how expression of EV contents correlates with the expression in their cells of origin, that is, correlation or anti‐correlation. A recent study that compared the transcriptome of prostate cancer tissue to paired uEV samples, showed that while the complexity for mRNA between sample types was comparable, a set of mRNAs were significantly enriched in uEV (Almeida et al., 2022 ). Moreover, the same study showed that uEV were enriched in mature cytoplasmic mRNA, which was confirmed also in vitro (Almeida et al., 2022 ).…”

“…A recent study that compared the transcriptome of prostate cancer tissue to paired uEV samples, showed that while the complexity for mRNA between sample types was comparable, a set of mRNAs were significantly enriched in uEV (Almeida et al., 2022 ). Moreover, the same study showed that uEV were enriched in mature cytoplasmic mRNA, which was confirmed also in vitro (Almeida et al., 2022 ). Hence, the applicability of tissue/single cell signatures for deconvolution are not straightforward.…”

Clinical application of pancreatic juice‐derived small extracellular vesicles of pancreatic ductal adenocarcinoma

“…All encapsulating cargos, including protein, nucleic acids and lipids, into various body fluids-derived sEVs can be targets for cancer-specific biomarkers, and their potential application in the noninvasive diagnosis of cancer, screening and monitoring of therapeutic responses is strongly expected. [34][35][36][37][38][39][40][41][42][43][44][45][46][47] Regarding the cargo of PJ-derived sEVs, miRNAs and proteins have been studied to identify candidates diagnostic biomarkers for PDAC Figure 1. [25][26][27][28][29] Nakamura et al identified miR-21 and miR-155 in PJ-derived sEVs as potential diagnostic biomarkers of PDAC.…”

Importance and implications of exosomes in nephrology and urology

“…Almeida et al extracted urinary EVs of PC patients using centrifugation, which they identified with NTA, EM, WB and RNA analyses. The comparison of total RNA-sequencing of FFPE PC tumor tissue and their paired urinary EV measurements highlighted strong differences in circRNA signals between tumor and EVs and suggests an important role of circRNAs in PC detection and treatment [ 4 ].…”