title: A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.
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.
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Schönhuber
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schuck
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Veltkamp
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schachtler
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zukowska
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Eser
authors.affiliation: German Cancer Research Center (DKFZ), Division for Cellular Immunology, Heidelberg, Germany.
authors.forename: Thorsten B
authors.initials: TB
authors.lastname: Feyerabend
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Mariel C
authors.initials: MC
authors.lastname: Paul
authors.affiliation: Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, München, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Eser
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Moores Cancer Center, Division of Surgical Oncology, University of California San Diego, La Jolla, California, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Ruby
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Fangtang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Chang-Lung
authors.initials: CL
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Everett J
authors.initials: EJ
authors.lastname: Moding
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Helmholtz Zentrum München, Research Unit Comparative Medicine, Neuherberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Scheideler
authors.affiliation: MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kind
authors.affiliation: Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: Angelika E
authors.initials: AE
authors.lastname: Schnieke
authors.affiliation: German Cancer Research Center (DKFZ), Division for Cellular Immunology, Heidelberg, Germany.
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.|Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009857:Oncogenes; D010179:Pancreas / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D057285:Precision Medicine / Q000379:methods*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D045522:Recombinases / Q000378:metabolism*; D015203:Reproducibility of Results; D013045:Species Specificity; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen; D013997:Time Factors
chemical_list: D045522:Recombinases; C485184:enhanced green fluorescent protein; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)