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    Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells.

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    Author
    Huijbers, IJ; Bin Ali, R; Pritchard, C; Cozijnsen, M; Kwon, M-C; Proost, N; Song, J-Y; de Vries, H; Badhai, J; Sutherland, K; ...
    Date
    2014-02
    Source Title
    EMBO Molecular Medicine
    Publisher
    EMBO
    University of Melbourne Author/s
    Sutherland, Kate
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
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    Document Type
    Journal Article
    Citations
    Huijbers, I. J., Bin Ali, R., Pritchard, C., Cozijnsen, M., Kwon, M. -C., Proost, N., Song, J. -Y., de Vries, H., Badhai, J., Sutherland, K., Krimpenfort, P., Michalak, E. M., Jonkers, J. & Berns, A. (2014). Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells.. EMBO Mol Med, 6 (2), pp.212-225. https://doi.org/10.1002/emmm.201303297.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255735
    DOI
    10.1002/emmm.201303297
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927956
    Abstract
    Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.

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