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A mouse model to identify cooperating signaling pathways in cancer

Nature Methods volume 9, pages 897–900 (2012)Cite this article

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Abstract

We here establish a mouse cancer model called Multi-Hit that allows for the evaluation of oncogene cooperativities in tumor development. The model is based on the stochastic expression of oncogene combinations ('hits') that are mediated by Cre in a given tissue. Cells with cooperating hits are positively selected and give rise to tumors. We used this approach to evaluate the requirement of Ras downstream effector pathways in tumorigenesis.

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Figure 1: The RasE Multi-Hit mouse model.
Figure 2: Lung adenocarcinomas in RasEAdCre mice.
Figure 3: Histopathological evaluation of lung tumors.

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Acknowledgements

We thank J. Downward (London Research Institute) for Ras effector mutants, A. Berns (Netherlands Cancer Institute) for Rosa26CreERT2 mice and G. Felsenfeld (National Institute of Diabetes and Digestive and Kidney Diseases, USA) for chicken 2xHS4 insulator sequences. We thank M. Sibilia and E.F. Wagner for critical reading of the manuscript and M. Mair and D. Khan for technical assistance. This work was supported by the Ludwig Boltzmann Gesellschaft (LBG), the Austrian Science Fund (FWF) grant SFB F28 to M. Müller, R.M. and R.E., the FWF Doktoratskolleg-plus grant 'Inflammation and Immunity' to M. Müller and R.E., the CCC Vienna Research grant to E.C. and R.E. and the Austrian Federal Ministry of Science and Research GENAU grant 'Austromouse' to M. Müller, T.R., J.M.P., E.C. and R.E. J.M.P. is supported by the Institute of Molecular Biotechnology (IMBA) and an advanced European Research Council (ERC) grant.

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Author notes

  1. Monica Musteanu, Leander Blaas, Emilio Casanova and Robert Eferl: These authors contributed equally to this work.

Authors and Affiliations

  1. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    Monica Musteanu, Leander Blaas, Rainer Zenz, Jasmin Svinka, Thomas Hoffmann, Beatrice Grabner, Hans-Peter Kantner, Richard Moriggl, Lukas Kenner, Dagmar Stoiber, Emilio Casanova & Robert Eferl

  2. Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Monica Musteanu

  3. Institute of Molecular Biotechnology, Vienna, Austria

    Daniel Schramek & Josef Martin Penninger

  4. Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria

    Mathias Müller

  5. Institute of Laboratory Animal Science and Biomodels Austria, University of Veterinary Medicine, Vienna, Austria

    Thomas Kolbe & Thomas Rülicke

  6. Department for Agrobiotechnology, Biotechnology in Animal Production, University of Natural Resources and Applied Life Sciences, Tulln, Austria

    Thomas Kolbe

  7. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

    Lukas Kenner

  8. Center of Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria

    Dagmar Stoiber

  9. Institute of Pathology, Medical University of Graz, Graz, Austria

    Helmut Popper

  10. Institute for Cancer Research (ICR), Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria

    Robert Eferl

Authors
  1. Monica Musteanu
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  2. Leander Blaas
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  14. Dagmar Stoiber
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  16. Helmut Popper
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  17. Emilio Casanova
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  18. Robert Eferl
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Contributions

M. Musteanu performed the study and interpreted data. L.B., R.Z., J.S., T.H., B.G. and D.S. provided major technical support. H.-P.K., M. Müller, T.K., T.R., R.M., L.K., D.S. and J.M.P. provided technical support. H.P. provided histopathological support and interpreted data. E.C. designed and supervised the study. R.E. designed and supervised the study, interpreted data and wrote the manuscript.

Corresponding author

Correspondence to Robert Eferl.

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The authors declare no competing financial interests.

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Musteanu, M., Blaas, L., Zenz, R. et al. A mouse model to identify cooperating signaling pathways in cancer. Nat Methods 9, 897–900 (2012). https://doi.org/10.1038/nmeth.2130

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