Abstract
Extracellular vesicles (EV) are considered as a potential tool for early disease diagnosis; however, factors modifying EV release remain partially unknown. By using patient-derived organoids that capture the cellular heterogeneity of epithelial tissues, here we studied the connection between the Wnt-producing microniche and EV secretion in multiple tissues. Although nearly all cells in pancreatic ductal (PD) and pancreatic ductal adenocarcinoma (PDAC) samples expressed porcupine (PORCN), an enzyme critical for Wnt secretion, only a subpopulation of lung bronchiolar (NL) and lung adenocarcinoma (LUAD) organoid cells produced active Wnt. The microniche for proliferating cells was shaped not only by PORCN + cells in NL and LUAD organoids but also by fibroblast-derived EVs. This effect could be blocked by using Wnt secretion inhibitors. Whereas inhibiting Wnt secretion in PD NL or LUAD organoids critically changed both cell proliferation and EV release, these were uncoupled from each other in PDAC. Sorting for CD133 identified a cell population in the LUAD microniche that produced organoids with a high percentage of PORCN + and proliferating cells and an elevated EV secretion, which may explain that CD133 marks LUAD cells with malignant behavior. Collectively, we show here that high cell proliferation rate, induced by Wnt pathway activation, is coupled to a higher EV release, a critical finding that may be considered when developing EV-based diagnostic tools.
Highlights
Extracellular vesicles (EV) are membrane-surrounded structures released by virtually all cell types
pancreatic ductal adenocarcinoma (PDAC), lung bronchiolar, and lung adenocarcinoma (LUAD) organoids, here we provide evidence that Wnt activity and cell proliferation are coupled to EV release in multiple normal tissue types, but not in all cancers
We provide evidence that Wnt activity and cell proliferation are coupled to an elevated secretion of EVs in organoids of various tissue origins
Summary
Extracellular vesicles (EV) are membrane-surrounded structures released by virtually all cell types. They carry biologically active molecules, such as RNAs, lipids, and proteins from the releasing to the target cells, providing a novel way of intercellular communication (Mathieu et al, 2019). EVs transport their cargo in a protected form. They contain molecules specific for the Extracellular Vesicles and Wnt Activation releasing cells at a high concentration in the body fluids and tissues. They provide a promising tool for early disease diagnosis. General mechanisms and factors modifying EV release remain poorly known
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