• An Erratum to this article was published on 07 April 2015

This article has been updated


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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  • 31 October 2014

     In the version of this article initially published online, affiliation 12 was missing for Roland Rad, Roland M. Schmid and Dieter Saur. The list should have read: “Roland Rad1,5,12,13, Roland M Schmid1,12,13 & Dieter Saur1,12,13.” The error has been corrected for the print, PDF and HTML versions of this article.


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The authors thank A. Berns (Netherlands Cancer Institute), S. Dymecki (Harvard Medical School), T. Jacks (Massachusetts Institute of Technology), L. Luo (Stanford University), J. Martinez-Barbera (University College London) and D. Tuveson (Cold Spring Harbor Laboratory) for providing transgenic animals, C. Wright (Vanderbilt University) for the mouse Pdx1 promoter construct, P. Soriano (Mount Sinai School of Medicine) for the Flp-o expression vector and the R26 targeting vector, T. Schmidt and M. Bewerunge-Hudler (DKFZ Microarray Core Facility) for mRNA analyses, and J. Götzfried, U. Götz and S. Jaeckel for technical assistance. This work was supported by funding from Deutsche Forschungsgemeinschaft (DFG SA 1374/4-1 to D.S. and SFB824, TP C9 to G.S. and D.S.), the Helmholtz Alliance Preclinical Comprehensive Cancer Center (to H.-R.R., R.R., R.M.S. and D.S.), the German Cancer Consortium (DKTK) (to R.R., R.M.S. and D.S.), the Wilhelm-Sander Foundation (2012.084.1 to G.S.), the Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal (I.V.), the European Union (ERC Advanced Grant No.233074 to H.-R.R.), and the National Cancer Institute USA (R01 CA138265 to D.G.K. and CA155620 to A.M.L.).

Author information

Author notes

    • Nina Schönhuber
    • , Barbara Seidler
    • , Kathleen Schuck
    •  & Christian Veltkamp

    These authors contributed equally to this work.


  1. Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany.

    • Nina Schönhuber
    • , Barbara Seidler
    • , Kathleen Schuck
    • , Christian Veltkamp
    • , Christina Schachtler
    • , Magdalena Zukowska
    • , Stefan Eser
    • , Mariel C Paul
    • , Sabine Klein
    • , Roland Rad
    • , Roland M Schmid
    • , Günter Schneider
    •  & Dieter Saur
  2. Division for Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Thorsten B Feyerabend
    •  & Hans-Reimer Rodewald
  3. Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, München, Germany.

    • Philipp Eser
  4. Moores Cancer Center, Division of Surgical Oncology, University of California San Diego, La Jolla, California, USA.

    • Andrew M Lowy
  5. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.

    • Ruby Banerjee
    • , Fangtang Yang
    • , Allan Bradley
    •  & Roland Rad
  6. Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.

    • Chang-Lung Lee
    •  & David G Kirsch
  7. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.

    • Everett J Moding
    •  & David G Kirsch
  8. Helmholtz Zentrum München, Research Unit Comparative Medicine, Neuherberg, Germany.

    • Angelika Scheideler
  9. MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK.

    • Dario R Alessi
  10. Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.

    • Ignacio Varela
  11. Livestock Biotechnology, Technische Universität München, Freising, Germany.

    • Alexander Kind
    •  & Angelika E Schnieke
  12. German Cancer Consortium (DKTK), Heidelberg, Germany.

  13. German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Roland Rad
    • , Roland M Schmid
    •  & Dieter Saur


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B.S. and D.S. designed research; N.S., B.S., K.S., C.V., C.S., M.Z., S.E., M.C.P., P.E., S.K., R.B., F.Y., A.S., I.V., R.R., G.S. and D.S., performed research; T.B.F., A.M.L., C.-L.L., E.J.M., D.G.K., A.S., D.R.A., I.V., A.B., A.K., A.E.S., H.-R.R., R.R. and R.M.S. contributed new reagents/analytic tools; N.S., B.S., K.S., C.V., C.S., M.Z., S.E., M.C.P., P.E., S.K., R.B., F.Y., I.V., R.R., G.S. and D.S. analyzed data; and B.S. and D.S. wrote the paper. N.S., B.S., K.S. and C.V. contributed equally to this manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dieter Saur.

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