Dataset Information

Proteomic analysis of serum EVs derived from PSC, CCA and PSC-CCA patients

ABSTRACT: Cholangiocarcinomas (CCAs) are heterogeneous biliary cancers with dismal prognosis. Their etiologies remain mostly unclear, although primary sclerosing cholangitis (PSC) is a well-known risk factor. There is an urgent need of accurate non-invasive biomarkers for early CCA diagnosis and to predict patient´s prognosis, which may improve their clinical management and outcome. Here, by high-throughput proteomic analysis of serum extracellular vesicles (EVs), we identified diagnostic and/or prognostic biomarkers specific for CCAs in patients with PSC, and others common to all CCA subtypes. Bulk RNA tissue transcriptomic data revealed that these biomarkers are predominantly expressed in hepatobiliary tissues, being expressed in different liver cell types. Furthermore, single-cell RNAseq (scRNA-seq) analysis revealed that the expression of these biomarkers was preferentially found in malignant cholangiocytes within CCA tumors. In summary, these results highlight the potential of serum EVs to reflect cancer presence, especially for difficult-to-diagnose malignancies, including CCA."

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

DISEASE(S): Primary Sclerosing Cholangitis,Cholangiocarcinoma

SUBMITTER: Mikel Azkargorta

LAB HEAD: Felix Elortza

PROVIDER: PXD026197 | Pride | 2023-07-20

REPOSITORIES: Pride

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Publications

Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma.

Lapitz Ainhoa A Azkargorta Mikel M Milkiewicz Piotr P Olaizola Paula P Zhuravleva Ekaterina E Grimsrud Marit M MM Schramm Christoph C Arbelaiz Ander A O'Rourke Colm J CJ La Casta Adelaida A Milkiewicz Malgorzata M Pastor Tania T Vesterhus Mette M Jimenez-Agüero Raul R Dill Michael T MT Lamarca Angela A Valle Juan W JW Macias Rocio I R RIR Izquierdo-Sanchez Laura L Pérez Castaño Ylenia Y Caballero-Camino Francisco Javier FJ Riaño Ioana I Krawczyk Marcin M Ibarra Cesar C Bustamante Javier J Nova-Camacho Luiz M LM Falcon-Perez Juan M JM Elortza Felix F Perugorria Maria J MJ Andersen Jesper B JB Bujanda Luis L Karlsen Tom H TH Folseraas Trine T Rodrigues Pedro M PM Banales Jesus M JM

Journal of hepatology 20230301 1

<h4>Background & aims</h4>Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs).<h4>Methods</h4>EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC ...[more]

PMID: 36868481

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Project description:Background & Aims: Cholangiocarcinomas (CCAs), heterogeneous biliary tumors with dismal prognosis, lack accurate early-diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods: EVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=42), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (n=34) and healthy individuals (n=55) were characterized by mass-spectrometry. Diagnostic biomarkers of PSC-CCA, non-PSC CCA or CCAs regardless etiology (pan-CCAs) were defined, and their expression was evaluated in human organs/tissues and within CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated. Results: High-throughput proteomics identified candidate diagnostic biomarkers for PSC-CCA, non-PSC CCA or pan-CCA, as well as and for differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning logit modelling disclosed CRP/FRIL/Fibrinogen algorithm with diagnostic value for early-stage PSC-CCA vs isolated PSC (AUC=0.944; OR=82.0), overpowering CA19-9 (AUC=0.735; OR=9.3). An algorithm combining CRP/VWF/PIGR/ /Fibrinogen allowed the diagnosis of early-stage non-PSC CCAs compared to healthy individuals (AUC=0.999; OR=1115). Noteworthy, levels of Fibrinogen/CRP/PIGR/FRIL showed predictive capacity for CCA development in patients with PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EVprognostic biomarkers independent to clinical features, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively. Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA, representing a novel tumor cell-derived liquid biopsy for personalized medicine.

			Action	DRS
	10_AT10_C10.msf	Msf
	10_AT10_C10.raw	Raw
	11_AT11_C11.msf	Msf
	11_AT11_C11.raw	Raw
	12_AT12_C12.msf	Msf