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Chimeric mouse tumor models reveal differences in pathway activation between ERBB family– and KRAS-dependent lung adenocarcinomas

Nature Biotechnology volume 28, pages 7178 (2010) | Download Citation

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Abstract

To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFRL858R and KRASG12V chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category.

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Acknowledgements

We thank S. Kollipara, I. Agekeum, Q. Xiao, D. Potz, K. Jesmer, Q. Shen, J. Brodeur and A. Cooper for their expert technical help. We also thank K. Garland, P. Bains-Vallee and S. Perry for excellent animal research support. The CCSP-rtTA construct was provided by J. Whitsett at the University of Cincinnati. Finally, we are grateful to R. O'Hagan for helpful discussions and critical reading of the manuscript.

Author information

Author notes

    • Yinghui Zhou
    •  & William M Rideout II

    These authors contributed equally to this work.

Affiliations

  1. AVEO Pharmaceuticals, Cambridge, Massachusetts, USA.

    • Yinghui Zhou
    • , William M Rideout II
    • , Tong Zi
    • , Angela Bressel
    • , Shailaja Reddypalli
    • , Rebecca Rancourt
    • , Jin-Kyeung Woo
    • , M Isabel Chiu
    • , Steven C Clark
    • , Murray O Robinson
    •  & Joerg Heyer
  2. Belfer Institute for Applied Cancer Science, Departments of Medical Onocology, Medicine and Genetics, Dana-Farber Cancer Institute and Department of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • James W Horner
    •  & Ronald A DePinho
  3. Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA.

    • Lynda Chin
  4. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Marcus Bosenberg
  5. Koch Institute and Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Tyler Jacks

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Contributions

Y.Z. established ES cell lines, analyzed the expression data and participated in data interpretation. W.M.R. established ES cell lines, chimeras and participated in data interpretation. T.Z. performed and analyzed immunohistochemistry. A.B. phenotyped and analyzed all mice. S.R. cloned all vectors and targeting constructs. R.R. established chimeric mice and phenotyped mice. J.-K.W. performed and analyzed RT-PCR and luciferase assays. J.W.H. established HER2 transgenic mice. M.B. performed all pathology analysis. L.C., M.I.C., S.C.C., R.A.D. and M.O.R. participated in the planning and data interpretation. T.J. and J.H. conceived the chimera model and participated in planning and data analysis. W.M.R., Y.Z., R.A.D. and J.H. wrote the manuscript and all authors edited it.

Competing interests

Y.Z., W.R., T.Z., A.B., I.C., S.C., M.R. and J.H. are employed by AVEO Pharmaceuticals. S.R., R.R. and J.K.W. are former employees of AVEO Pharmaceuticals. J.W.H. and M.B. are consultants to AVEO Pharmaceuticals. L.C., T.J. and R.D.P. are founders and advisors to AVEO Pharmaceuticals.

Corresponding author

Correspondence to Joerg Heyer.

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DOI

https://doi.org/10.1038/nbt.1595

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