Dataset Information

Combined expression of plasma CA19-9 and thrombospondin-2 for accurate diagnosis of pancreatic cancer and distal cholangiocarcinoma– A proteome approach

ABSTRACT: Minimally- invasive diagnostic biomarkers for patients with pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (CCA) are warranted to enhance early and accurate diagnosis. This study identified tumor tissue secreted proteins, the “secretome”, which was analysed for differential candidate diagnostic plasma proteins. Secretome of tumor and normal tissue was collected directly after resection of the primary tumor from 4 patients with PDAC and distal CCA. The tissue secretome was investigated by label-free LC-MSMS, and database searching identified a total of 5179 proteins. 696 proteins were differentially enriched in tumor secretome compared to normal tissue. Thrombospondin-2 (THBS2) emerged as most promising candidate diagnostic biomarker. Subsequent analysis of THBS2 in plasma samples of patients with PDAC and distal CCA by ELISA showed significantly higher abundance compared to healthy individuals (p<0.001) and resulted in an AUC of 0.844.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Ductal Adenocarcinoma Cell, Pancreatic Ductal Adenocarcinoma Cell Line, Epithelial Cell

DISEASE(S): Pancreas Adenocarcinoma

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD012480 | Pride | 2020-05-26

REPOSITORIES: Pride

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Publications

Combined Expression of Plasma Thrombospondin-2 and CA19-9 for Diagnosis of Pancreatic Cancer and Distal Cholangiocarcinoma: A Proteome Approach.

Le Large Tessa Y S TYS Meijer Laura L LL Paleckyte Rosita R Boyd Lenka N C LNC Kok Bart B Wurdinger Thomas T Schelfhorst Tim T Piersma Sander R SR Pham Thang V TV van Grieken Nicole C T NCT Zonderhuis Barbara M BM Daams Freek F van Laarhoven Hanneke W M HWM Bijlsma Maarten F MF Jimenez Connie R CR Giovannetti Elisa E Kazemier Geert G

The oncologist 20200114 4

<h4>Background</h4>Minimally invasive diagnostic biomarkers for patients with pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (dCCA) are warranted to facilitate accurate diagnosis. This study identified diagnostic plasma proteins based on proteomics of tumor secretome.<h4>Materials and methods</h4>Secretome of tumor and normal tissue was collected after resection of PDAC and dCCA. Differentially expressed proteins were measured by mass spectrometry. Selected candidate bioma ...[more]

PMID: 31943574

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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of appropriate preclinical models to test novel anticancer strategies. We developed four orthotopic mouse models employing primary human PDAC cells expressing Firefly and Gaussia luciferases, enabling bioluminescence monitoring of tumor growth and metastasis formation. Additional tumor characterization was performed using MR and high frequency ultrasound imaging. Genomic and immunohistochemical analysis revealed c-Met amplification and overexpression in one of four models. Analysis of c-Met inhibitors in vitro showed that crizotinib had the most potent effect. Moreover, we demonstrated synergistic effects between crizotinib and gemcitabine M-bM-^@M-^S the standard of care therapeutic in PDAC patients - in vitro and in vivo. Importantly, crizotinib reduced the cytidine deaminase activity in PDAC cells causing prolonged activity of gemcitabine due to diminished metabolic inactivation, as measured by LC-MS/MS. This might at least in part explain the observed prolonged survival of concomitantly treated mice with PDAC tumors and metastases. In conclusion, our orthotopic PDAC models enabled PDAC tumor imaging, and showed genetic, histopathological and metastatic features similar to their originator tumors. This allowed the identification of c-Met as a potential therapeutic target in PDAC, and revealed a cytidine deaminase-mediated synergistic mechanism between crizotinib and gemcitabine, a combination of drugs that warrants further investigation for the potential treatment of PDAC patients. 12 test samples in total [4 PDAC models (PDAC-1, PDAC-2, PDAC-3, PDAC-4; in three panel: primary human PDAC, primary tumor culture and mouse sample)] and reference sample (healthy control (mix/pool of healthy volunteers DNA) were analyzed as following (8 hybridizations); PDAC-1 primary human-Cy3 vs PDAC-4 cultured cells -Cy5 PDAC-1 cultured cells-Cy3 vs PDAC-4 mouse-Cy5 PDAC-1 mouse-Cy3 vs reference-Cy5 PDAC-2 primary human-Cy3 vs reference-Cy5 PDAC-2_cultured cells-Cy3 vs PDAC-2 mouse-Cy5 PDAC-3_primary human-Cy3 vs reference-Cy5 PDAC-3_cultured cells-Cy3 vs PDAC-3 mouse-Cy5 PDAC-4 primary human-Cy5 vs reference-Cy3 Normalized log2 ratio of (sample/references) data were calculated for 12 samples [*txt files on Series records]. Description of experimental/analysis design in r-program to generate 12 samples from 8 raw data files is provided in README.txt [Series supplementary file]

Dataset Information

Combined expression of plasma CA19-9 and thrombospondin-2 for accurate diagnosis of pancreatic cancer and distal cholangiocarcinoma– A proteome approach

Publications

Combined Expression of Plasma Thrombospondin-2 and CA19-9 for Diagnosis of Pancreatic Cancer and Distal Cholangiocarcinoma: A Proteome Approach.

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