Proteogenomic Network Analysis of Context-Specific KRAS Signaling in Mouse-to-Human Cross-Species Translation.
Animals
Carcinogenesis
Carcinoma, Pancreatic Ductal
/ genetics
Cellular Microenvironment
Colorectal Neoplasms
/ genetics
Computational Biology
Datasets as Topic
Disease Models, Animal
Gene Regulatory Networks
Humans
Metabolic Networks and Pathways
Mice
Mutation
/ genetics
Protein Biosynthesis
Proteogenomics
/ methods
Proto-Oncogene Proteins p21(ras)
/ genetics
Signal Transduction
Tumor Microenvironment
ASL
CDK2
KRAS
MET
SMAD3
cancer
colon
pancreas
phosphoproteomics
proteomics
species-translation
Journal
Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080
Informations de publication
Date de publication:
25 09 2019
25 09 2019
Historique:
received:
30
12
2018
revised:
01
06
2019
accepted:
15
07
2019
pubmed:
16
9
2019
medline:
12
9
2020
entrez:
16
9
2019
Statut:
ppublish
Résumé
The highest frequencies of KRAS mutations occur in colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). The ability to target downstream pathways mediating KRAS oncogenicity is limited by an incomplete understanding of the contextual cues modulating the signaling output of activated K-RAS. We performed mass spectrometry on mouse tissues expressing wild-type or mutant Kras to determine how tissue context and genetic background modulate oncogenic signaling. Mutant Kras dramatically altered the proteomes and phosphoproteomes of preneoplastic and neoplastic colons and pancreases in a context-specific manner. We developed an approach to statistically humanize the mouse networks with data from human cancer and identified genes within the humanized CRC and PDAC networks synthetically lethal with mutant KRAS. Our studies demonstrate the context-dependent plasticity of oncogenic signaling, identify non-canonical mediators of KRAS oncogenicity within the KRAS-regulated signaling network, and demonstrate how statistical integration of mouse and human datasets can reveal cross-species therapeutic insights.
Identifiants
pubmed: 31521603
pii: S2405-4712(19)30238-8
doi: 10.1016/j.cels.2019.07.006
pmc: PMC6816257
mid: NIHMS1535066
pii:
doi:
Substances chimiques
KRAS protein, human
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
258-270.e6Subventions
Organisme : NCI NIH HHS
ID : U01 CA215798
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA243163
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA199252
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA195744
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK098285
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132129
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA184427
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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