A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas.
Adaptor Proteins, Signal Transducing
/ metabolism
Adenocarcinoma
/ metabolism
Animals
Carcinoma, Pancreatic Ductal
/ metabolism
Cell Cycle Proteins
/ metabolism
Cell Differentiation
Cell Lineage
Cell Proliferation
DNA Methylation
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HCT116 Cells
Homeostasis
Humans
Mice
Proto-Oncogene Proteins c-myc
/ metabolism
Proto-Oncogene Proteins p21(ras)
/ metabolism
SOXB1 Transcription Factors
/ metabolism
Transcription Factors
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
YAP-Signaling Proteins
Kras
Myc
Sox2
Yap
p53
pancreatic cancer
tumor maintenance
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
07 10 2019
07 10 2019
Historique:
received:
16
01
2019
revised:
19
05
2019
accepted:
19
07
2019
pubmed:
27
8
2019
medline:
28
5
2020
entrez:
27
8
2019
Statut:
ppublish
Résumé
Employing inducible genetically engineered and orthotopic mouse models, we demonstrate a key role for transcriptional regulator Yap in maintenance of Kras-mutant pancreatic tumors. Integrated transcriptional and metabolomics analysis reveals that Yap transcribes Myc and cooperates with Myc to maintain global transcription of metabolic genes. Yap loss triggers acute metabolic stress, which causes tumor regression while inducing epigenetic reprogramming and Sox2 upregulation in a subset of pancreatic neoplastic cells. Sox2 restores Myc expression and metabolic homeostasis in Yap-deficient neoplastic ductal cells, which gradually re-differentiate into acinar-like cells, partially restoring pancreatic parenchyma in vivo. Both the short-term and long-term effects of Yap loss in inducing cell death and re-differentiation, respectively, are blunted in advanced, poorly differentiated p53-mutant pancreatic tumors. Collectively, these findings reveal a highly dynamic and interdependent metabolic, transcriptional, and epigenetic regulatory network governed by Yap, Myc, Sox2, and p53 that dictates pancreatic tumor metabolism, growth, survival, and differentiation.
Identifiants
pubmed: 31447265
pii: S1534-5807(19)30628-8
doi: 10.1016/j.devcel.2019.07.022
pmc: PMC6783361
mid: NIHMS1535640
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
KRAS protein, human
0
MYC protein, human
0
Myc protein, mouse
0
Proto-Oncogene Proteins c-myc
0
SOX2 protein, human
0
SOXB1 Transcription Factors
0
Sox2 protein, mouse
0
TP53 protein, human
0
Transcription Factors
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Yap1 protein, mouse
0
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
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
113-128.e9Subventions
Organisme : NCI NIH HHS
ID : P30 CA051008
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA187090
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009686
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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