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A mouse model to identify cooperating signaling pathways in cancer


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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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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Authors and Affiliations



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.

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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).

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