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A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells

Although cancer‐derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighbouring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on re...

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Autores principales: Hinzman, Charles P., Singh, Baldev, Bansal, Shivani, Li, Yaoxiang, Iliuk, Anton, Girgis, Michael, Herremans, Kelly M., Trevino, Jose G., Singh, Vijay K., Banerjee, Partha P., Cheema, Amrita K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164146/
https://www.ncbi.nlm.nih.gov/pubmed/35656858
http://dx.doi.org/10.1002/jev2.12232
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author Hinzman, Charles P.
Singh, Baldev
Bansal, Shivani
Li, Yaoxiang
Iliuk, Anton
Girgis, Michael
Herremans, Kelly M.
Trevino, Jose G.
Singh, Vijay K.
Banerjee, Partha P.
Cheema, Amrita K.
author_facet Hinzman, Charles P.
Singh, Baldev
Bansal, Shivani
Li, Yaoxiang
Iliuk, Anton
Girgis, Michael
Herremans, Kelly M.
Trevino, Jose G.
Singh, Vijay K.
Banerjee, Partha P.
Cheema, Amrita K.
author_sort Hinzman, Charles P.
collection PubMed
description Although cancer‐derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighbouring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on recipient non‐tumourigenic pancreatic normal epithelial cells upon internalization. We demonstrate that cEVs are readily internalized and induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in treated normal pancreatic epithelial cells within 24 h. We further show that PDAC cEVs increase cell proliferation, migration, and invasion and that these changes are regulated at least in part, by the UPR mediator DDIT3. Subsequently, these cells release several inflammatory cytokines. Leveraging a layered multi‐omics approach, we analysed EV cargo from a panel of six PDAC and two normal pancreas cell lines, using multiple EV isolation methods. We found that cEVs were enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including palmitic acid, sphingomyelins, metabolic regulators of tRNA charging and proteins which regulate trafficking and degradation. We further show that palmitic acid, at doses relevant to those found in cEVs, is sufficient to induce ER stress in normal pancreas cells. These results suggest that cEV cargo packaging may be designed to disseminate proliferative and invasive characteristics upon internalization by distant recipient normal cells, hitherto unreported. This study is among the first to highlight a major role for PDAC cEVs to induce stress in treated normal pancreas cells that may modulate a systemic response leading to altered phenotypes. These findings highlight the importance of EVs in mediating disease aetiology and open potential areas of investigation toward understanding the role of cEV lipids in promoting cell transformation in the surrounding microenvironment.
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spelling pubmed-91641462022-06-04 A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells Hinzman, Charles P. Singh, Baldev Bansal, Shivani Li, Yaoxiang Iliuk, Anton Girgis, Michael Herremans, Kelly M. Trevino, Jose G. Singh, Vijay K. Banerjee, Partha P. Cheema, Amrita K. J Extracell Vesicles Research Articles Although cancer‐derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighbouring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on recipient non‐tumourigenic pancreatic normal epithelial cells upon internalization. We demonstrate that cEVs are readily internalized and induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in treated normal pancreatic epithelial cells within 24 h. We further show that PDAC cEVs increase cell proliferation, migration, and invasion and that these changes are regulated at least in part, by the UPR mediator DDIT3. Subsequently, these cells release several inflammatory cytokines. Leveraging a layered multi‐omics approach, we analysed EV cargo from a panel of six PDAC and two normal pancreas cell lines, using multiple EV isolation methods. We found that cEVs were enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including palmitic acid, sphingomyelins, metabolic regulators of tRNA charging and proteins which regulate trafficking and degradation. We further show that palmitic acid, at doses relevant to those found in cEVs, is sufficient to induce ER stress in normal pancreas cells. These results suggest that cEV cargo packaging may be designed to disseminate proliferative and invasive characteristics upon internalization by distant recipient normal cells, hitherto unreported. This study is among the first to highlight a major role for PDAC cEVs to induce stress in treated normal pancreas cells that may modulate a systemic response leading to altered phenotypes. These findings highlight the importance of EVs in mediating disease aetiology and open potential areas of investigation toward understanding the role of cEV lipids in promoting cell transformation in the surrounding microenvironment. John Wiley and Sons Inc. 2022-06-03 2022-06 /pmc/articles/PMC9164146/ /pubmed/35656858 http://dx.doi.org/10.1002/jev2.12232 Text en © 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Hinzman, Charles P.
Singh, Baldev
Bansal, Shivani
Li, Yaoxiang
Iliuk, Anton
Girgis, Michael
Herremans, Kelly M.
Trevino, Jose G.
Singh, Vijay K.
Banerjee, Partha P.
Cheema, Amrita K.
A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
title A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
title_full A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
title_fullStr A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
title_full_unstemmed A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
title_short A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
title_sort multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164146/
https://www.ncbi.nlm.nih.gov/pubmed/35656858
http://dx.doi.org/10.1002/jev2.12232
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