TY - JOUR T1 - Centrosome amplification mediates small extracellular vesicles secretion via lysosome disruption JF - bioRxiv DO - 10.1101/2020.08.19.257162 SP - 2020.08.19.257162 AU - Sophie D. Adams AU - Judit Csere AU - Gisela D’angelo AU - Edward P. Carter AU - Teresa Arnandis AU - Martin Dodel AU - Hemant Kocher AU - Richard Grose AU - Graça Raposo AU - Faraz Mardakheh AU - Susana A. Godinho Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/08/20/2020.08.19.257162.abstract N2 - 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 EV 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 SEV 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.Competing Interest StatementThe authors have declared no competing interest. ER -