Suppression of Lung Adenocarcinoma Progression by Nkx2-1

Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-p...

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Main Authors:	Winslow, Monte M., Dayton, Talya L., Verhaak, Roel G. W., Kim-Kiselak, Caroline, Snyder, Eric L., Feldser, David M., Hubbard, Diana D., DuPage, Michel J., Whittaker, Charles A., Hoersch, Sebastian, Yoon, Stephanie, Crowley, Denise, Bronson, Roderick T., Chiang, Derek Y., Meyerson, Matthew, Jacks, Tyler
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088778/

id	pubmed-3088778
recordtype	oai_dc
spelling	pubmed-30887782011-11-05 Suppression of Lung Adenocarcinoma Progression by Nkx2-1 Winslow, Monte M. Dayton, Talya L. Verhaak, Roel G. W. Kim-Kiselak, Caroline Snyder, Eric L. Feldser, David M. Hubbard, Diana D. DuPage, Michel J. Whittaker, Charles A. Hoersch, Sebastian Yoon, Stephanie Crowley, Denise Bronson, Roderick T. Chiang, Derek Y. Meyerson, Matthew Jacks, Tyler Article Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3–5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain-and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6–9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor. 2011-04-06 2011-05-05 /pmc/articles/PMC3088778/ /pubmed/21471965 http://dx.doi.org/10.1038/nature09881 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Winslow, Monte M. Dayton, Talya L. Verhaak, Roel G. W. Kim-Kiselak, Caroline Snyder, Eric L. Feldser, David M. Hubbard, Diana D. DuPage, Michel J. Whittaker, Charles A. Hoersch, Sebastian Yoon, Stephanie Crowley, Denise Bronson, Roderick T. Chiang, Derek Y. Meyerson, Matthew Jacks, Tyler
spellingShingle	Winslow, Monte M. Dayton, Talya L. Verhaak, Roel G. W. Kim-Kiselak, Caroline Snyder, Eric L. Feldser, David M. Hubbard, Diana D. DuPage, Michel J. Whittaker, Charles A. Hoersch, Sebastian Yoon, Stephanie Crowley, Denise Bronson, Roderick T. Chiang, Derek Y. Meyerson, Matthew Jacks, Tyler Suppression of Lung Adenocarcinoma Progression by Nkx2-1
author_facet	Winslow, Monte M. Dayton, Talya L. Verhaak, Roel G. W. Kim-Kiselak, Caroline Snyder, Eric L. Feldser, David M. Hubbard, Diana D. DuPage, Michel J. Whittaker, Charles A. Hoersch, Sebastian Yoon, Stephanie Crowley, Denise Bronson, Roderick T. Chiang, Derek Y. Meyerson, Matthew Jacks, Tyler
author_sort	Winslow, Monte M.
title	Suppression of Lung Adenocarcinoma Progression by Nkx2-1
title_short	Suppression of Lung Adenocarcinoma Progression by Nkx2-1
title_full	Suppression of Lung Adenocarcinoma Progression by Nkx2-1
title_fullStr	Suppression of Lung Adenocarcinoma Progression by Nkx2-1
title_full_unstemmed	Suppression of Lung Adenocarcinoma Progression by Nkx2-1
title_sort	suppression of lung adenocarcinoma progression by nkx2-1
description	Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3–5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain-and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6–9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088778/
_version_	1611452143238119424

Suppression of Lung Adenocarcinoma Progression by Nkx2-1

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