Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis
Ainhoa Lapitz,
Ander Arbelaiz,
Colm J. O’Rourke,
Jose L. Lavin,
Adelaida La Casta,
Cesar Ibarra,
Juan P. Jimeno,
Alvaro Santos-Laso,
Laura Izquierdo-Sanchez,
Marcin Krawczyk,
Maria J. Perugorria,
Raul Jimenez-Aguero,
Alberto Sanchez-Campos,
Ioana Riaño,
Esperanza Gónzalez,
Frank Lammert,
Marco Marzioni,
Rocio I.R. Macias,
Jose J. G. Marin,
Tom H. Karlsen,
Luis Bujanda,
Juan M. Falcón-Pérez,
Jesper B. Andersen,
Ana M. Aransay,
Pedro M. Rodrigues,
Jesus M. Banales
Affiliations
Ainhoa Lapitz
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Ander Arbelaiz
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Colm J. O’Rourke
Biotech Research & Innovation Centre (BRIC), Department of Health and Medical Sciences, 2200, Copenhagen, Denmark
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Cesar Ibarra
Hospital of Cruces, 48903, Bilbao, Spain
Juan P. Jimeno
“Complejo Hospitalario de Navarra”, 31008, Pamplona, Spain
Alvaro Santos-Laso
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Laura Izquierdo-Sanchez
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Marcin Krawczyk
Department of Medicine II, Saarland University Medical Centre, Saarland University, 66421, Homburg, Germany
Maria J. Perugorria
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Raul Jimenez-Aguero
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Alberto Sanchez-Campos
Hospital of Cruces, 48903, Bilbao, Spain
Ioana Riaño
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Esperanza Gónzalez
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Exosomes Laboratory, 48160, Derio, Spain
Frank Lammert
Department of Medicine II, Saarland University Medical Centre, Saarland University, 66421, Homburg, Germany
Marco Marzioni
“Università Politecnica delle Marche”, Department of Gastroenterology, 60121, Ancona, Italy
Rocio I.R. Macias
Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220, Madrid, Spain
Jose J. G. Marin
Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220, Madrid, Spain
Tom H. Karlsen
Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, 0372, Oslo, Spain
Luis Bujanda
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Juan M. Falcón-Pérez
Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220, Madrid, Spain
Jesper B. Andersen
Biotech Research & Innovation Centre (BRIC), Department of Health and Medical Sciences, 2200, Copenhagen, Denmark
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
Jesus M. Banales
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014, San Sebastian, Spain
: Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers.
