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GEO help: Mouse over screen elements for information. |
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Status |
Public on Jan 27, 2011 |
Title |
Suppression of Lung Adenocarcinoma Progression by Nkx2-1 |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
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.
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Overall design |
23 cell lines derived from primary tumor or metastasis. 6 samples analyzed to determine the effect of Nkx2-1 knockdown on gene expression
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Contributor(s) |
Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, Hubbard DD, DuPage MJ, Whittaker CA, Hoersch S, Yoon S, Crowley D, Bronson RT, Chiang DY, Meyerson M, Jacks T |
Citation(s) |
21471965 |
Submission date |
Jan 26, 2011 |
Last update date |
Mar 06, 2018 |
Contact name |
Charles Arthur Whittaker |
E-mail(s) |
charliew@mit.edu
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Organization name |
Koch Institute
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Street address |
77 Mass Ave 76-189
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City |
Cambridge |
State/province |
MA |
ZIP/Postal code |
02152 |
Country |
USA |
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Platforms (1) |
GPL6096 |
[MoEx-1_0-st] Affymetrix Mouse Exon 1.0 ST Array [transcript (gene) version] |
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Samples (29)
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Relations |
BioProject |
PRJNA136113 |
Supplementary file |
Size |
Download |
File type/resource |
GSE26874_MoEx-1_0-st-v1._core+miRNA+RfSq+UCSC_.SH.2916.mps.txt.gz |
1.5 Mb |
(ftp)(http) |
TXT |
GSE26874_MoEx-1_0-st-v1._core+miRNA+RfSq+UCSC_.SH.2916.ps.txt.gz |
778.6 Kb |
(ftp)(http) |
TXT |
GSE26874_MoEx-1_0-st-v1.r2.pgf.gz |
80.6 Mb |
(ftp)(http) |
PGF |
GSE26874_RAW.tar |
673.9 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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