Plasma Extracellular Vesicle Characteristics Correlate with Tumor Differentiation and Predict Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgery with Curative Intent

Abstract

Better preoperative characterization of patients with pancreatic ductal adenocarcinoma (PDAC) would aid in treatment optimization. Extracellular vesicles (EV) are promising, largely unexplored biomarkers in PDAC. This study aimed to evaluate if plasma EV characteristics are associated with PDAC clinical characteristics and overall survival (OS). The prospective cohort included 34 PDAC patients undergoing surgery with curative intent. Patient data and plasma samples were collected preoperatively, intraoperatively and one month postoperatively. Small plasma EV (sEV) concentration and size were determined by nanoparticle-tracking analysis. A Mann–Whitney test, Spearman’s rho and Cox regression were used in statistical analysis. Preoperatively, patients with poorly differentiated tumors had significantly larger plasma sEVs when compared to patients with well/moderately differentiated tumors (mean diameter 176.9 vs. 149.2 nm, p = 0.021), the sEV size even enabling discrimination of the two groups (AUC = 0.742, 95% CI = 0.560–0.923). Plasma sEV characteristics were also a predictor of OS in multivariable analysis. Patients with a more than 33.8% increase in sEV concentration after one month had 7.2 months shorter median OS (p = 0.002), while patients with a more than 28.0% decrease in sEV size had 9.2 months shorter median OS (p = 0.045). Plasma sEV concentration and size correlate with tumor differentiation and may predict OS in PDAC patients. In the future, plasma sEV characteristics could contribute to improved patient stratification for optimized treatment.

Single Extracellular VEsicle Nanoscopy

“…Compared to healthy control (Figures 5 and S12), PDAC patients had (1) smaller CD9-enriched EVs; (2) larger and rounder IGF1R-enriched EVs with more tetraspanin molecules. Interestingly, recent data (Badovinac et al, 2021) indicates that PDAC patients with poorly differentiated resectable tumours had significantly larger plasma EVs. This suggests that the biogenesis or clearance of these EV populations may be affected.…”

Blood Nanoparticles – Influence on Extracellular Vesicle Isolation and Characterization

“…As well as such changes in their molecular composition in blood, the EV concentrations and size profile might be linked to physiological factors like hypoxia, autophagy or stress, and hence be typical for a diverse set of diseases ( Vasconcelos et al, 2019 ). Indeed, increases in plasma EV levels have been reported in connection with several cancers ( Navarro et al, 2019 ; Badovinac et al, 2021 ), and also for cardiovascular and autoimmune diseases ( Dickhout and Koenen, 2018 ; Maione et al, 2020 ).…”

Extracellular Vesicle-Based Detection of Pancreatic Cancer

“…EV based serum diagnostics provides an additional and powerful diagnostic component in the field of liquid biopsies (Yee et al, 2020). With regard to EV diagnostic in PDAC, the concentration and size of EVs in patient serum has been correlated with tumor differentiation and overall survival in PDAC patients (Badovinac et al, 2021), but no specific cargo analysis of "diagnostic" EVs in serum has been reported up to now. In this respect, our results provide some novelties: First of all, we identified ADAM8, a protease with a therapeutic potential in PDAC, to be located in EVs that meet all criteria for exosomes.…”