Stage-specific sensitivity to p53 restoration during lung cancer progression
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Hemann_Stage specific.pdf
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1.67 MB
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Author(s)
Feldser, David M.
Kostova, Kamena K.
Winslow, Monte Meier
Taylor, Sarah E.
Cashman, Chris
Whittaker, Charles A.
Resnick, Rebecca
Bronson, Roderick T.
Hemann, Michael
Sanchez-Rivera, Francisco Jav
Date Issued
November 2010
Journal
Nature
Publisher
Nature Publishing Group
Citation
Feldser, David M. et al. “Stage-specific Sensitivity to P53 Restoration During Lung Cancer Progression.” Nature 468.7323 (2010): 572–575.
Version
Author's final manuscript
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.
Description
2011 May 25
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike 3.0
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DOI of Published Version
https://doi.org/10.1038/nature09535
