Protein Kinase D1, Reduced in Human Pancreatic Tumors, Increases Secretion of Small Extracellular Vesicles From Cancer Cells That Promote Metastasis to Lung in Mice.
Animals
Carcinogenesis
/ pathology
Carcinoma, Pancreatic Ductal
/ blood
Cell Line, Tumor
Cell Movement
Datasets as Topic
Down-Regulation
Extracellular Vesicles
/ metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Lung
/ pathology
Lung Neoplasms
/ blood
Mice
Mice, Knockout
Neoplasm Invasiveness
/ pathology
Oligonucleotide Array Sequence Analysis
Pancreas
/ pathology
Pancreatic Neoplasms
/ blood
Phosphorylation
Primary Cell Culture
Protein Kinase C
/ deficiency
Xenograft Model Antitumor Assays
Cytoskeletal Organization
Cytoskeleton
Invasion
Multivesicular Bodies
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
26
08
2019
revised:
21
04
2020
accepted:
13
05
2020
pubmed:
25
5
2020
medline:
16
4
2021
entrez:
25
5
2020
Statut:
ppublish
Résumé
Pancreatic tumor cells release small extracellular vesicles (sEVs, exosomes) that contain lipids and proteins, RNA, and DNA molecules that might promote formation of metastases. It is not clear what cargo these vesicles contain and how they are released. Protein kinase D1 (PRKD1) inhibits cell motility and is believed to be dysregulated in pancreatic ductal adenocarcinomas. We investigated whether it regulates production of sEVs in pancreatic cancer cells and their ability to form premetastatic niches for pancreatic cancer cells in mice. We analyzed data from UALCAN and human pancreatic tissue microarrays to compare levels of PRKD1 between tumor and nontumor tissues. We studied mice with pancreas-specific disruption of Prkd1 (PRKD1 Levels of PRKD1 were reduced in human pancreatic ductal adenocarcinoma tissues compared with nontumor tissues. PRKD1 Human pancreatic ductal adenocarcinoma has reduced levels of PRKD1 compared with nontumor pancreatic tissues. Loss of PRKD1 results in reduced phosphorylation of cortactin in pancreatic cancer cell lines, resulting in increased in F-actin at the plasma membrane and increased release of sEVs, with altered content. These sEVs promote metastasis of xenograft and pancreatic tumors to lung in mice.
Sections du résumé
BACKGROUND & AIMS
Pancreatic tumor cells release small extracellular vesicles (sEVs, exosomes) that contain lipids and proteins, RNA, and DNA molecules that might promote formation of metastases. It is not clear what cargo these vesicles contain and how they are released. Protein kinase D1 (PRKD1) inhibits cell motility and is believed to be dysregulated in pancreatic ductal adenocarcinomas. We investigated whether it regulates production of sEVs in pancreatic cancer cells and their ability to form premetastatic niches for pancreatic cancer cells in mice.
METHODS
We analyzed data from UALCAN and human pancreatic tissue microarrays to compare levels of PRKD1 between tumor and nontumor tissues. We studied mice with pancreas-specific disruption of Prkd1 (PRKD1
RESULTS
Levels of PRKD1 were reduced in human pancreatic ductal adenocarcinoma tissues compared with nontumor tissues. PRKD1
CONCLUSIONS
Human pancreatic ductal adenocarcinoma has reduced levels of PRKD1 compared with nontumor pancreatic tissues. Loss of PRKD1 results in reduced phosphorylation of cortactin in pancreatic cancer cell lines, resulting in increased in F-actin at the plasma membrane and increased release of sEVs, with altered content. These sEVs promote metastasis of xenograft and pancreatic tumors to lung in mice.
Identifiants
pubmed: 32446697
pii: S0016-5085(20)34705-3
doi: 10.1053/j.gastro.2020.05.052
pii:
doi:
Substances chimiques
protein kinase D
EC 2.7.10.-
Protein Kinase C
EC 2.7.11.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1019-1035.e22Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.