title: Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer.
abstract: Rapid and reliable diagnosis of prostate cancer (PCa) is highly desirable as current used methods lack specificity. In addition, identification of PCa biomarkers that can classify patients into high- and low-risk groups for disease progression at early stage will improve treatment decision-making. Here, we describe a set of protein-combination panels in urinary extracellular vesicles (EVs), defined by targeted proteomics and immunoblotting techniques that improve early non-invasive detection and stratification of PCa patients.We report a two-protein combination in urinary EVs that classifies benign and PCa patients (ADSV-TGM4), and a combination of five proteins able to significantly distinguish between high- and low-grade PCa patients (CD63-GLPK5-SPHM-PSA-PAPP). Proteins composing the panels were validated by immunohistochemistry assays in tissue microarrays (TMAs) confirming a strong link between the urinary EVs proteome and alterations in PCa tissues. Moreover, ADSV and TGM4 abundance yielded a high diagnostic potential in tissue and promising TGM4 prognostic power. These results suggest that the proteins identified in urinary EVs distinguishing high- and low grade PCa are a reflection of histological changes that may be a consequence of their functional involvement in PCa development. In conclusion, our study resulted in the identification of protein-combination panels present in urinary EVs that exhibit high sensitivity and specificity for PCa detection and patient stratification. Moreover, our study highlights the potential of targeted proteomic approaches-such as selected reaction monitoring (SRM)-as diagnostic assay for liquid biopsies via urinary EVs to improve diagnosis and prognosis of suspected PCa patients.
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Sequeiros
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Rigau
authors.affiliation: Proteomics Unit, Centre de Regulació Genòmica (CRG), Barcelona, Spain.|Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiva
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Melania
authors.initials: M
authors.lastname: Montes
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Garcia-Grau
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Sherley
authors.initials: S
authors.lastname: Diaz
authors.affiliation: Department of Urology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Celma
authors.affiliation: Department of Urology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Bijnsdorp
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Campos
authors.affiliation: Sagetis-Biotech; Grup d'Enginyeria de Materials (GEMAT) Institut Químic de Sarrià, Barcelona, Spain.
authors.forename: Primiano
authors.initials: P
authors.lastname: Di Mauro
authors.affiliation: Sagetis-Biotech; Grup d'Enginyeria de Materials (GEMAT) Institut Químic de Sarrià, Barcelona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Borrós
authors.affiliation: Departement of Basic Science, International University of Catalonia, Barcelona, Spain.|IDIBELL-Bellvitge Biomedical Research Institute, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Reventós
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Doll
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Paciucci
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Pegtel
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.|Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: de Torres
authors.affiliation: Proteomics Unit, Centre de Regulació Genòmica (CRG), Barcelona, Spain.|Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sabidó
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.|Department of Urology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Morote
authors.affiliation: Group of Biomedical Research in Urology, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Olivan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000652:urine*; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000652:urine; D040901:Proteomics / Q000379:methods*; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor
keywords: biomarkers; diagnosis; extracellular vesicles; prostate cancer; urine