Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
13
05
2021
accepted:
10
01
2022
revised:
16
12
2021
pubmed:
23
1
2022
medline:
19
4
2022
entrez:
22
1
2022
Statut:
ppublish
Résumé
Metastases are often the direct cause of death from pancreatic ductal adenocarcinoma (PDAC). The role of genomic alterations (GA) in mediating tropism and metastasis formation by PDAC cells is currently unknown. We aimed to identify GAs predisposing colonization of PDAC cells to the liver and decipher mechanisms enabling this process. In order to reveal specific genes, we studied the frequency of GA in 8,880 local and 7,983 metastatic PDAC samples. We observed differential pattern of GA in the local tumor and specific metastatic sites, with liver metastases characterized by deletion of CDKN2A/B (encoding p16/p15, respectively). The role of CDKN2A/B in promoting liver metastasis was evidenced by enhanced tumorigenic phenotype of p15/p16-deleted PDAC cells when exposed to hepatocytes conditioned media. The liver is characterized by high-ammonia low-glutamine environment and transcriptomic assays indicated unique adaptation of PDAC cells to these conditions, including regulation of genes leading to reduced glutaminolysis, like overexpression of GLUL and reduction in GLS2. Furthermore, metabolic assays indicated an increase in glutamate derived from [U-
Identifiants
pubmed: 35064215
doi: 10.1038/s41388-022-02184-2
pii: 10.1038/s41388-022-02184-2
doi:
Substances chimiques
CDKN2A protein, human
0
CDKN2B protein, human
0
Cyclin-Dependent Kinase Inhibitor p15
0
Cyclin-Dependent Kinase Inhibitor p16
0
Ammonia
7664-41-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1468-1481Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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