Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma sampl
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology Anikó Zeöld1 · Gyöngyvér Orsolya Sándor1 · Anna Kiss1 · András Áron Soós1 · Tamás Tölgyes2 · Attila Bursics2 · Ákos Szűcs3 · László Harsányi3 · Ágnes Kittel4 · András Gézsi5,6 · Edit I. Buzás5,7,8 · Zoltán Wiener1 Received: 12 May 2020 / Revised: 13 October 2020 / Accepted: 3 November 2020 © The Author(s) 2020
Abstract 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 patientderived 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. Keywords PDAC · Collagen · Extracellular matrix · Organoid · Exosome · miR-21 · miR-195
Introduction
Anikó Zeöld, Gyöngyvér Orsolya Sándor contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03703-8) contains supplementary material, which is available to authorized users. * Zoltán Wiener [email protected]‑univ.hu 1
Department of Genetics, Cell and Immunobiology, Molecular Cancer Biology Research Group, Semmelweis University, Budapest, Hungary
2
Uzsoki Hospital, Budapest, Hungary
3
1st Department of Surgery, Semmelweis University, Budapest, Hungary
4
Institute of Experimental Medicine, Eötvös Loránd Research Network, Budapest, Hungary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most dangerous cancers with a 5-year survival rate of less than 8%. Although novel promising targets have been identified [1], there is only a slow progress in the early diagnosis and treatment efficiency of this disease. Most PDAC tumors prevalently harbour mutati
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