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Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon

Nature Genetics volume 40, pages 600–608 (2008)Cite this article

Abstract

Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-RasG12D in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-RasG12D did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.

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Figure 1: Mutant K-Ras, but not mutant N-Ras, promotes hyperplastic growth in the colonic epithelium.
Figure 2: K-RasG12D promotes hyperproliferation through Mek.
Figure 3: Activated N-Ras, but not K-Ras, suppresses DSS-induced apoptosis in the colonic epithelium.
Figure 4: Mutationally activated K-Ras suppresses differentiation in Apc-mutant colon cancers.
Figure 5: Attenuated MAPK signaling in tumors expressing mutant K-Ras.
Figure 6: K-RasG12D signals through Raf, but not Mek, to promote tumor proliferation.

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Acknowledgements

The authors thank A. Charest and A. Shaw for critically reading the manuscript, A. Ventura, J. Keller and U. McDermott for technical advice and D. Lauffenburger and M. McMahon for helpful discussion. This work was supported by US National Institutes of Health grants U01-CA84306 and U54-CA112967 to T.J., K01-CA118425 to K.H., and U01-CA84221 and R01-CA72614 to K.S., grants from the Association pour la Recherche sur le Cancer, Ligue Nationale Contre le Cancer, and Inserm to M.G., and partially by the Cancer Center Support (Core) grant P30-CA14051 from the National Cancer Institute. K.H. was a Robert Black Fellow of the Damon Runyon Cancer Research Foundation and was supported by a Career Development award from the Harvard GI SPORE grant from the National Cancer Institute (P50-CA127003). T.J. is a Howard Hughes Medical Institute Investigator and a Daniel K. Ludwig Scholar. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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Authors and Affiliations

  1. Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Kevin M Haigis, Ann Cheung & Tyler Jacks

  2. Massachusetts General Hospital, Center for Cancer Research and Molecular Pathology Unit, Charlestown, 02129, Massachusetts, USA

    Kevin M Haigis, Krystle R Kendall, Yufang Wang & Jeffrey Settleman

  3. Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Marcia C Haigis

  4. Department of Pathology, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Jonathan N Glickman

  5. Institut National de la Santé et de la Recherche Médicale U674, Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain et Institut Universitaire d'Hématologie, Paris, France

    Michiko Niwa-Kawakita & Marco Giovannini

  6. Department of Pediatrics and Cancer Biology Program, Stanford University School of Medicine, Palo Alto, 94305, California, USA

    Alejandro Sweet-Cordero

  7. JS Leopold Consulting, Ann Arbor, 48105, Michigan, USA

    Judith Sebolt-Leopold

  8. Department of Pediatrics, University of California San Francisco, San Francisco, California, 94143, USA

    Kevin M Shannon

  9. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Tyler Jacks

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  1. Kevin M Haigis
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Contributions

K.M.H. and T.J. conceived and designed the experiments. K.M.H., K.R.K., Y.W., A.C., M.C.H. and A.S.-C. performed the experiments. J.N.G. consulted on pathological analysis of samples. K.M.H. and T.J. analyzed the data. M.N.-K. and M.G. generated and provided conditionally mutant Apc mice. J.S.-L. and K.M.S. provided CI-1040. J.S. provided AZ628 and Sorafenib. K.M.H. and T.J. wrote the manuscript.

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Correspondence to Tyler Jacks.

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Competing interests

Judith Sebolt–Leopold is a former employee and shareholder of Pfizer, the maker of CI–1040

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Supplementary Note, Supplementary Methods, Supplementary Table 1, Supplemenary Figures 1–4 (PDF 5123 kb)

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Haigis, K., Kendall, K., Wang, Y. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet 40, 600–608 (2008). https://doi.org/10.1038/ng.115

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