Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology

• Published in: Cellular and molecular life sciences : CMLS Vol. 78; no. 6; pp. 3005 - 3020
• Main Authors: Zeöld, Anikó, Sándor, Gyöngyvér Orsolya, Kiss, Anna, Soós, András Áron, Tölgyes, Tamás, Bursics, Attila, Szűcs, Ákos, Harsányi, László, Kittel, Ágnes, Gézsi, András, Buzás, Edit I., Wiener, Zoltán
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2021; Springer Nature B.V
• Subjects: Adenocarcinoma; Animals; Antibiotics; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood; Blood plasma; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cargo; Case-Control Studies; CD63 antigen; Cell Biology; Cells, Cultured; Collagen; Collagen (type I); Collagen Type I - metabolism; Collagen Type I - pharmacology; Cytokines - pharmacology; Epidermal growth factor; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular vesicles; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Heterogeneity; Humans; In vivo methods and tests; Kinases; Life Sciences; Mice; Mice, Inbred C57BL; MicroRNAs - blood; MicroRNAs - metabolism; miRNA; Mutation; Organoids; Organoids - cytology; Organoids - drug effects; Organoids - metabolism; Original; Original Article; Pancreas; Pancreatic cancer; Pancreatic Ducts - cytology; Pancreatic Ducts - metabolism; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatitis; Pancreatitis - genetics; Pancreatitis - metabolism; Pancreatitis - pathology; Patients; Plasma; Tumors; PDAC; Exosome; Collagen; Extracellular matrix; Organoid; miR-195; miR-21
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-020-03703-8

Extracellular vesicles (EV) are considered as a promising diagnostic tool for pancreatic ductal adenocarcinoma (PDAC), a disease with a poor 5-year survival that has not improved in the past years. PDAC patient-derived 3D organoids maintain the intratumoral cellular heterogeneity, characteristic for the tumor in vivo.Thus, they represent an ideal in vitro model system to study human cancers. Here we show that the miRNA cargo of EVs from PDAC organoids largely differs among patients. However, we detected a common set of EV miRNAs that were present in matched organoids and blood plasma samples of individual patients. Importantly, the levels of EV miR-21 and miR-195 were higher in PDAC blood EV preparations than in healthy controls, albeit we found no difference compared to chronic pancreatitis (CP) samples. In addition, here we report that the accumulation of collagen I, a characteristic change in the extracellular matrix (ECM) in both CP and PDAC, largely increases EV release from pancreatic ductal organoids. This provides a possible explanation why both CP and PDAC patient-derived plasma samples have an elevated amount of CD63 + EVs. Collectively, we show that PDAC patient-derived organoids represent a highly relevant model to analyze the cargo of tumor cell-derived EVs. Furthermore, we provide evidence that not only driver mutations, but also changes in the ECM may critically modify EV release from pancreatic ductal cells.