Abstract
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.
Highlights
Pancreatic cancer includes both exocrine and endocrine tumors, of which the majority are pancreatic ductal adenocarcinomas (PDACs)—one of the most aggressive and lethal human cancers among solid malignancies [1]
According to the meta-analysis study design and inclusion and exclusion criteria (Figure 1), 20 secretome studies and 35 proteome studies in pancreatic cancer were selected, which reported protein data obtained by mass spectrometry (Tables 1 and 2) [3,6,29,34,37,41,43,45,46,47,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]
Among the 43 proteins verified by SignalP, SecretomeP, Exocarta, Vesiclepedia, TargetP, and TMHMM, the proteins Vimentin (VIM), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and Superoxide dismutase 2 (SOD2)
Summary
Pancreatic cancer includes both exocrine and endocrine tumors, of which the majority are pancreatic ductal adenocarcinomas (PDACs)—one of the most aggressive and lethal human cancers among solid malignancies [1]. Due to its poor prognosis, with the number of deaths (n = 432,000). Nearly equivalent to the number of cases (n = 459,000), pancreatic cancer is the seventh leading cause of cancer death [2]. Less than 5% of patients survive up to 5 years after diagnosis [3,4]. Because of the asymptomatic nature of the early stages of the disease and the lack of efficient methods for its detection, most patients with pancreatic cancer have locally advanced and inoperable disease at diagnosis [5,6]. About 90% of the PDAC cases are complex due to distant metastases [7,8]. Less than 20% of patients are candidates for complete surgical removal, and even after treatment, most relapse and die within a year [11]
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