Docking Protein p130Cas Regulates Acinar to Ductal Metaplasia During Pancreatic Adenocarcinoma Development and Pancreatitis.
Acinar Cells
/ pathology
Adenocarcinoma
/ pathology
Animals
Carcinogenesis
Carcinoma, Pancreatic Ductal
/ pathology
Cell Transformation, Neoplastic
/ pathology
Crk-Associated Substrate Protein
/ metabolism
Genome-Wide Association Study
Humans
Metaplasia
/ pathology
Mice
Pancreatic Neoplasms
/ pathology
Pancreatitis
/ chemically induced
Phosphatidylinositol 3-Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Proto-Oncogene Proteins p21(ras)
/ metabolism
Pancreatic Neoplasms
ADM
Carcinogenesis
Kras
Metaplasia
PDAC
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
29
06
2021
revised:
18
11
2021
accepted:
12
12
2021
pubmed:
20
12
2021
medline:
3
5
2022
entrez:
19
12
2021
Statut:
ppublish
Résumé
Acinar to ductal metaplasia is the prerequisite for the initiation of Kras-driven pancreatic ductal adenocarcinoma (PDAC), and candidate genes regulating this process are emerging from genome-wide association studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines; however, its role in PDAC development has remained largely unknown. Human PDAC samples and murine Kras We found that high expression of p130Cas is frequently detected in PDAC and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by means of repressing PI3K-AKT signaling, even in the presence of a worsening condition like pancreatitis. Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for acinar to ductal metaplasia and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.
Sections du résumé
BACKGROUND & AIMS
Acinar to ductal metaplasia is the prerequisite for the initiation of Kras-driven pancreatic ductal adenocarcinoma (PDAC), and candidate genes regulating this process are emerging from genome-wide association studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines; however, its role in PDAC development has remained largely unknown.
METHODS
Human PDAC samples and murine Kras
RESULTS
We found that high expression of p130Cas is frequently detected in PDAC and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by means of repressing PI3K-AKT signaling, even in the presence of a worsening condition like pancreatitis.
CONCLUSIONS
Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for acinar to ductal metaplasia and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.
Identifiants
pubmed: 34922945
pii: S0016-5085(21)04077-4
doi: 10.1053/j.gastro.2021.12.242
pii:
doi:
Substances chimiques
BCAR1 protein, human
0
Crk-Associated Substrate Protein
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1242-1255.e11Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.