A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.
Nat Med
; 20(11): 1340-1347, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25326799
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Engenharia Genética
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Carcinoma Ductal Pancreático
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Recombinases
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Medicina de Precisão
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Terapia de Alvo Molecular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article