Centrosome amplification mediates small extracellular vesicles secretion via lysosome disruption

Abstract

Bidirectional communication between cells and their surrounding environment is critical in both normal and pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules between cells, are recognized as an important constituent of cell-cell communication. In cancer, alterations in EVs secretion contribute to the growth and metastasis of tumor cells. However, the mechanisms underlying these changes remain largely unknown. Here, we show that centrosome amplification is associated with and sufficient to promote small extracellular vesicle (SEV) secretion in pancreatic cancer cells. This is a direct result due of lysosomal dysfunction, caused by increased reactive oxygen species (ROS) downstream of extra centrosomes. Defects in lysosome function promotes multivesicular body fusion with the plasma membrane, thereby enhancing SEVs secretion. Furthermore, we find that SEVs secreted in response to amplified centrosomes are functionally distinct and activate pancreatic stellate cells (PSCs). These activated PSCs promote the invasion of pancreatic cancer cells in heterotypic 3-D cultures. We propose that SEVs secreted by cancer cells with amplified centrosomes influence the bidirectional communication between the tumor cells and the surrounding stroma to promote malignancy.

Extracellular Vesicles as Drug Vectors for Precise Cancer Treatment

“…Exposure to the calcium ionophore ionomycin can also increase exosome secretion via the same mechanism [100]. It has been reported that lysosome dysfunction prevents efficient lysosome and multivesicular body fusion, which will promote EV secretion [101]. Through incubating cells with 20 mM ammonium chloride for up to 7 days, or with 200 nM bafilomycin A1 for up to 72 h, Alvarez-Erviti et al achieved lysosomal inhibition of human neuroblastoma cells SH-SY5Y, leading to an increase in exosome release [102].…”

Roles of exosomes in cancer chemotherapy resistance, progression, metastasis and immunity, and their clinical applications (Review)

“…Numerous cancer types usually show defects in the structure and number of centrosomes. Research reports have shown that the presence of excessive centrosomes can increase the secretion of exosomes, and that lysosomal dysfunction causes cells with extra centrosomes to secrete more exosomes in PDAC (108,109).…”

Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer

“…Secretion of ligands such as FGF2, PDGF, TGF-β, CSF-1 and CTGF by activated PSCs has been shown to promote cancer cell proliferation and invasion [ 18 , 19 , 20 , 21 ]. Extra-cellular vesicles may act as carriers for many of the growth factors [ 22 ]. Reversal of PSC activation, by All-trans retinoic acid (ATRA) or tamoxifen, can decrease actomyosin contractility and, therefore, prevent ECM remodeling and invasion, as well as reducing cancer cell proliferation [ 15 , 23 , 24 ].…”