Suppression of lung adenocarcinoma progression by Nkx2-1
Open accessAbstract
Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating 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 NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or 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. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, 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.
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Hemizygous Nkx2-1 loss suppresses EgfrL858R-driven lung carcinogenesis.
“hemizygous Nkx2–1 loss suppresses EgfrL858R-driven lung carcinogenesis”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [125]
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- Authors
- Winslow, M. M., Dayton, T. L., Verhaak, R. G. W., Kim-Kiselak, C., Snyder, E. L., Feldser, D. M., Hubbard, D. D., DuPage, M. J., Whittaker, C. A., Hoersch, S., Yoon, S., Crowley, D., Bronson, R. T., Chiang, D. Y., Meyerson, M., & Jacks, T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Broad Institute (US)
- Tufts University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Nature
- Published
- 2011-04-06
- Volume
- 473
- Issue
- 7345
- Pages
- 101-104
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3088778
- OpenAlex
- W2146040216
- Cited by
- 467
- References
- 51
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 23 · 2023: 29 · 2022: 31 · 2021: 37 · 2020: 27 · 2019: 44 · 2018: 24 · 2017: 25 · 2016: 27 · 2015: 30 · 2014: 34 · 2013: 40 · 2012: 29
- FWCI
- 19.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (T32HL007627)
- National Cancer Institute (R01CA109038, U01-CA84306, K99CA151968, K08CA154784, R00CA151968, U01CA084306, P30CA014051, P30-CA-14051)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- TTF-1, lung adenocarcinoma, tumor progression, metastasis, HMGA2, KRAS, p53 deficiency, transcriptional repression, gene expression signatures, tumor differentiation, suppressor genes, lung cancer prognosis, cross-species comparison
- MeSH terms
- Thyroid Nuclear Factor 1, Adenocarcinoma of Lung, Adenocarcinoma, Animals, Cell Differentiation, Disease Models, Animal, Humans, Lung Neoplasms, Nuclear Proteins, Transcription Factors, Down-Regulation, Gene Expression Regulation, Neoplastic, HMGA2 Protein, Cell Line, Tumor, Mice
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