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Nat Med. 2014 Nov;20(11):1340-1347. doi: 10.1038/nm.3646. Epub 2014 Oct 19.

A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.

Author information

1
Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
2
German Cancer Research Center (DKFZ), Division for Cellular Immunology, Heidelberg, Germany.
3
Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, München, Germany.
4
Moores Cancer Center, Division of Surgical Oncology, University of California San Diego, La Jolla, California, USA.
5
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
6
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.
7
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
8
Helmholtz Zentrum München, Research Unit Comparative Medicine, Neuherberg, Germany.
9
MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK.
10
Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
11
Livestock Biotechnology, Technische Universität München, Freising, Germany.
12
German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
#
Contributed equally

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.

PMID:
25326799
PMCID:
PMC4270133
DOI:
10.1038/nm.3646
[Indexed for MEDLINE]
Free PMC Article

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