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A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.
Nat. Med. 20, 1340-1347 (2014)
Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.
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Publication type
Article: Journal article
Document type
Scientific Article
Language
english
Publication Year
2014
HGF-reported in Year
2014
ISSN (print) / ISBN
1078-8956
e-ISSN
1546-170X
Journal
Nature medicine
Quellenangaben
Volume: 20,
Issue: 11,
Pages: 1340-1347
Publisher
Nature Publishing Group
Publishing Place
New York, NY
Reviewing status
Peer reviewed
Institute(s)
CF Comparative Medicine (AVM)
POF-Topic(s)
30202 - Environmental Health
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-500900-001
PubMed ID
25326799
DOI
10.1038/nm.3646
WOS ID
WOS:000344724300025
Scopus ID
84964314145
Erfassungsdatum
2014-10-20