Abstract
Due to a grim prognosis, there is an urgent need to detect pancreatic ductal adenocarcinoma (PDAC) prior to metastasis. However, reliable diagnostic imaging methods or biomarkers for PDAC or its precursor lesions are still scarce. ADAM8, a metalloprotease-disintegrin, is highly expressed in PDAC tissue and negatively correlates with patient survival. The aim of our study was to determine the ability of ADAM8-positive extracellular vesicles (EVs) and cargo microRNAs (miRNAs) to discriminate precursor lesions or PDAC from healthy controls. In order to investigate enrichment of ADAM8 on EVs, these were isolated from serum of patients with PDAC (n = 52), precursor lesions (n = 7) and healthy individuals (n = 20). Nanoparticle Tracking Analysis and electron microscopy indicated successful preparation of EVs that were analyzed for ADAM8 by FACS. Additionally, EV cargo analyses of miRNAs from the same serum samples revealed the presence of miR-720 and miR-451 by qPCR and was validated in 20 additional PDAC samples. Statistical analyses included Wilcoxon rank test and ROC curves. FACS analysis detected significant enrichment of ADAM8 in EVs from patients with PDAC or precursor lesions compared to healthy individuals (p = 0.0005). ADAM8-dependent co-variates, miR-451 and miR-720 were also diagnostic, as patients with PDAC had significantly higher serum levels of miR-451 and lower serum levels of miR-720 than healthy controls and reached high sensitivity and specificity (AUC = 0.93 and 1.00, respectively) to discriminate PDAC from healthy control. Thus, detection of ADAM8-positive EVs and related cargo miR-720 and miR-451 may constitute a specific biomarker set for screening individuals at risk for PDAC.
Highlights
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the world with an incidence of 45 in 100,000 and a 5-year survival rate of around 9% (Siegel et al, 2020)
Since ADAM8 is located on extracellular vesicles (EVs) as shown by bead-coupled FACS analysis, we investigated whether ADAM8 confers enzymatic activity to EVs enriched in ADAM8
By establishing a bead-supported FACS analysis method to analyze surface located ADAM8 in EVs, we demonstrated that ADAM8-positive EVs were significantly enriched in pancreatic ductal adenocarcinoma (PDAC) patients and were gradually increased with increasing tumor staging, at least when comparing precursor lesions with fully developed adenocarcinoma
Summary
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the world with an incidence of 45 in 100,000 and a 5-year survival rate of around 9% (Siegel et al, 2020). A number of factors are responsible for the poor prognosis of PDAC that combines the difficulties in detecting the tumor in early stages, an aggressive biological behavior to account. To detect PDAC in early stages, only a few biomarkers are used routinely that are able to detect its presence and the lesions prior to its derivation (Bartsch et al, 2018). Exosomes are a defined type of extracellular vesicle (EV) ranging in size from 30 to 100 nm and secreted by all cell types including cancer cells. In the context of cancer, exosomes produced in tumor cells contain an abundance of cell-specific molecules that may facilitate the discrimination between cancer afflicted patients and healthy individuals (Sumrin et al, 2018)
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