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Whether small extracellular vesicles (sEVs) can reflect bladder cancer molecular subtypes is unknown. We performed whole transcriptome RNA sequencing for formalin fixed paraffin embedded (FFPE) tumour tissues and sEVs separated from matched tissue explants, urine and plasma in patients with bladder cancer. sEVs were separated using size\u2010exclusion chromatography, and characterized by transmission electron microscopy, nano flow cytometry and western blots, respectively. High yield of sEVs were obtained using approximately 1\u00a0g of tissue, incubated with media for 30\u00a0min. FFPE tumour tissue and tumour tissue\u2010derived sEVs demonstrated good concordance in molecular subtype classification. All urinary sEVs were classified as luminal subtype, while all plasma sEVs were classified as Ba\/Sq subtype, regardless of the molecular subtypes indicated by their matched FFPE tumour tissue. The comparison within urine sEVs, which may exclude the sample type specific background, could pick up the different biology between NMIBC and MIBC, as well as the signature genes related to molecular subtypes. Four candidate sEV\u2010related bladder cancer\u2010specific mRNA biomarkers, FAM71E2, OR4K5, FAM138F and KRTAP26\u20101, were identified by analysing matched urine sEVs, tumour tissue derived sEVs, and adjacent normal tissue derived sEVs. Compared to sEVs separated from biofluids, tissue\u2010derived sEVs may reflect more tissue\u2010 or disease\u2010specific biological features. Urine sEVs are promising biomarkers to be used for liquid biopsy\u2010based molecular subtype classification, but the current algorithm needs to be modified\/adjusted. Future work is needed to validate the four new bladder cancer\u2010specific biomarkers in large cohorts.<\/jats:p>","DOI":"10.1002\/jev2.12402","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T04:06:06Z","timestamp":1706673966000},"source":"Crossref","is-referenced-by-count":19,"title":["Tumour tissue\u2010derived small extracellular vesicles reflect molecular subtypes of bladder cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7689-3237","authenticated-orcid":false,"given":"Liang","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Urology Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"The Brady Urological Institute Johns Hopkins University School of Medicine  Baltimore Maryland 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