Dataset Information

Comparison of the tumor cell secretome and patient sera for an accurate serum-based diagnosis of pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic cancer is the currently most lethal malignancy. Toward an accurate diagnosis of the disease in body liquids, we studied the protein composition of the secretomes of 16 primary and established cell lines of pancreatic ductal adenocarcinoma (PDAC). Compared to the secretome of non-tumorous cells, 112 proteins exhibited significantly different abundances. Functionally, the proteins were associated with PDAC features, such as decreased apoptosis, better cell survival and immune cell regulation. The result was compared to profiles obtained from 164 serum samples from two independent cohorts - a training and a test set - of patients with PDAC or chronic pancreatitis and healthy donors. Eight of the 112 secretome proteins exhibited similar variations in their abundance in the serum profile specific for PDAC patients, which was composed of altogether 189 proteins. The 8 markers shared by secretome and serum yielded a 95.1% accuracy of distinguishing PDAC from healthy in a Receiver Operating Characteristic curve analysis, while any number of serum-only markers produced substantially less accurate results. Utility of the identified markers was confirmed by classical enzyme linked immunosorbent assays (ELISAs). The study highlights the value of cell secretome analysis as a means of defining reliable serum biomarkers.

SUBMITTER: Mustafa S

PROVIDER: S-EPMC5355318 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Comparison of the tumor cell secretome and patient sera for an accurate serum-based diagnosis of pancreatic ductal adenocarcinoma.

Mustafa Shakhawan S Pan Longqiang L Marzoq Aseel A Fawaz Malak M Sander Laureen L Rückert Felix F Schrenk Andrea A Hartl Christina C Uhler Rico R Yildirim Adem A Strobel Oliver O Hackert Thilo T Giese Nathalia N Büchler Markus W MW Hoheisel Jörg D JD Alhamdani Mohamed Saiel Saeed MS

Oncotarget 20170201 7

Pancreatic cancer is the currently most lethal malignancy. Toward an accurate diagnosis of the disease in body liquids, we studied the protein composition of the secretomes of 16 primary and established cell lines of pancreatic ductal adenocarcinoma (PDAC). Compared to the secretome of non-tumorous cells, 112 proteins exhibited significantly different abundances. Functionally, the proteins were associated with PDAC features, such as decreased apoptosis, better cell survival and immune cell regul ...[more]

PMID: 28060763

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Project description:Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is extremely aggressive, has an unfavorable prognosis, and there are no biomarkers for early detection of the disease or identification of individuals at high risk for morbidity or mortality. The cellular and molecular complexity of PDAC leads to inconsistences in clinical validations of many proteins that have been evaluated as prognostic biomarkers of the disease. The tumor secretome, a potential source of biomarkers in PDAC, plays a crucial role in cell proliferation and metastasis, as well as in resistance to treatments, which together contribute to a worse clinical outcome. The massive amount of proteomic data from pancreatic cancer that has been generated from previous studies can be integrated and explored to uncover secreted proteins relevant to the diagnosis and prognosis of the disease. The present study aimed to perform an integrated meta-analysis of PDAC proteome and secretome public data to identify potential biomarkers of the disease. Our meta-analysis combined mass spectrometry data obtained from two systematic reviews of the pancreatic cancer literature, which independently selected 20 studies of the secretome and 35 of the proteome. Next, we predicted the secreted proteins using seven in silico tools or databases, which identified 39 secreted proteins shared between the secretome and proteome data. Notably, the expression of 31 genes of these secretome-related proteins was upregulated in PDAC samples from The Cancer Genome Atlas (TCGA) when compared to control samples from TCGA and The Genotype-Tissue Expression (GTEx). The prognostic value of these 39 secreted proteins in predicting survival outcome was confirmed using gene expression data from four PDAC datasets (validation set). The gene expression of these secreted proteins was able to distinguish high- and low-survival patients in nine additional tumor types from TCGA, demonstrating that deregulation of these secreted proteins may also contribute to the prognosis in multiple cancers types. Finally, we compared the prognostic value of the identified secreted proteins in PDAC biomarkers studies from the literature. This analysis revealed that our gene signature performed equally well or better than the signatures from these previous studies. In conclusion, our integrated meta-analysis of PDAC proteome and secretome identified 39 secreted proteins as potential biomarkers, and the tumor gene expression profile of these proteins in patients with PDAC is associated with worse overall survival.

Dataset Information

Comparison of the tumor cell secretome and patient sera for an accurate serum-based diagnosis of pancreatic ductal adenocarcinoma.

Publications

Comparison of the tumor cell secretome and patient sera for an accurate serum-based diagnosis of pancreatic ductal adenocarcinoma.

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