Abstract
Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1,2,3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.
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References
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000)
Selivanova, G. & Wiman, K. G. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene 26, 2243–2254 (2007)
Wang, W. & El-Deiry, W. S. Restoration of p53 to limit tumor growth. Curr. Opin. Oncol. 20, 90–96 (2008)
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007)
Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006)
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo . Nature 445, 661–665 (2007)
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a . Cell 88, 593–602 (1997)
Palmero, I., Pantoja, C. & Serrano, M. p19ARF links the tumour suppressor p53 to Ras. Nature 395, 125–126 (1998)
Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998)
Tuveson, D. A. et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004)
Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nature Genet. 40, 600–608 (2008)
Sarkisian, C. J. et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nature Cell Biol. 9, 493–505 (2007)
Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras . Genes Dev. 15, 3243–3248 (2001)
Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001)
Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322, 78–80 (1986)
Bremner, R. & Balmain, A. Genetic changes in skin tumor progression: correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell 61, 407–417 (1990)
Liu, M. L. et al. Amplification of Ki-ras and elevation of MAP kinase activity during mammary tumor progression in C3(1)/SV40 Tag transgenic mice. Oncogene 17, 2403–2411 (1998)
Junttila, M. R. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours Nature doi:10.1038/nature09526. (this issue)
Young, N. P. & Jacks, T. Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras. Proc. Natl Acad. Sci. USA 107, 10184–10189 (2010)
Lane, D. P. p53, guardian of the genome. Nature 358, 15–16 (1992)
Meylan, E. et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature 462, 104–107 (2009)
Dickins, R. A. et al. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nature Genet. 37, 1289–1295 (2005)
Bolstad, B. M., Collin, F., Simpson, K. M., Irizarry, R. A. & Speed, T. P. Experimental design and low-level analysis of microarray data. Int. Rev. Neurobiol. 60, 25–58 (2004)
Bolstad, B. M., Irizarry, R. A., Gautier, L. & Wu, Z. in Bioinformatics and Computational Biology Solutions using R and Bioconductor (eds Gentleman, R., Carey, V., Huber, W., Irizarry, R. & Dudoit, S. ) Ch. 2, 13–32 (Springer, 2005)
Smyth, G. K., Michaud, J. & Scott, H. S. Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics 21, 2067–2075 (2005)
Suzuki, R. & Shimodaira, H. Pvclust: an R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 22, 1540–1542 (2006)
Acknowledgements
We would like to thank M. DuPage and C. Kim for critical reading of the manuscript. We are indebted to D. Crowley, E. Vasile and M. Griffin at the Koch Institute Core facilities (supported by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute). We are grateful to M. Luo for microarray support. We thank M. Leversha at MSKCC for FISH. D.M.F. has been supported by the American Cancer Society (New England Area Fellow), and is a current Fellow of the Leukemia and Lymphoma Society. K.K.K. is supported by the John Reed Fund of the MIT undergraduate research program. M.M.W. was a Merck Fellow of the Damon Runyon Cancer Research Foundation and a Genentech postdoctoral fellow. T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. The Howard Hughes Medical Institute supported this work.
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D.M.F. and T.J. conceived of the experiments and wrote the manuscript with comments from all authors; D.M.F., K.K.K, C.C., S.E.T. and R.R. performed the experiments and analysed the data; M.M.W. and F.J.S.-R. gave conceptual advice; R.B. performed histological evaluations; C.A.W. performed bioinformatics data analysis; and M.T.H. provided reagents and conceptual advice.
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Gene expression data was deposited in Gene Expression Omnibus (GSE23875).
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Feldser, D., Kostova, K., Winslow, M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010). https://doi.org/10.1038/nature09535
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DOI: https://doi.org/10.1038/nature09535
