Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model.
Adenocarcinoma
/ genetics
Animals
Barrett Esophagus
/ genetics
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p16
/ genetics
Environmental Exposure
/ adverse effects
Esophageal Neoplasms
/ genetics
Humans
Methylnitrosourea
/ toxicity
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mutation
Neoplasms, Experimental
/ chemically induced
Organoids
/ pathology
Precancerous Conditions
/ genetics
Stomach Neoplasms
/ drug therapy
Tumor Suppressor Protein p53
/ genetics
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
01
07
2019
accepted:
18
12
2019
pubmed:
7
2
2020
medline:
14
4
2020
entrez:
7
2
2020
Statut:
ppublish
Résumé
Somatic alterations in cancer genes are being detected in normal and premalignant tissue, thus placing greater emphasis on gene-environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional and functional evaluation of gastric premalignancy. Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response inhibitors. These findings demonstrate the utility of mouse models that integrate genomic alterations with relevant exposures and highlight the importance of gene-environment interactions in shaping the premalignant state.
Identifiants
pubmed: 32025000
doi: 10.1038/s41588-019-0574-9
pii: 10.1038/s41588-019-0574-9
pmc: PMC7031028
mid: NIHMS1546989
doi:
Substances chimiques
Cdkn2a protein, mouse
0
Cyclin-Dependent Kinase Inhibitor p16
0
TP53 protein, human
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
Methylnitrosourea
684-93-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
219-230Subventions
Organisme : NIDDK NIH HHS
ID : K08 DK120930
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA163059
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127003
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK109209
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA098101
Pays : United States
Commentaires et corrections
Type : CommentIn
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doi: 10.1038/sdata.2014.35