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Series GSE26874 Query DataSets for GSE26874
Status Public on Jan 27, 2011
Title Suppression of Lung Adenocarcinoma Progression by Nkx2-1
Organism Mus musculus
Experiment type Expression profiling by array
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.
 
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
 
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
Organization name Koch Institute
Street address 77 Mass Ave 76-189
City Cambridge
State/province MA
ZIP/Postal code 02152
Country USA
 
Platforms (1)
GPL6096 [MoEx-1_0-st] Affymetrix Mouse Exon 1.0 ST Array [transcript (gene) version]
Samples (29)
GSM661546 373T1
GSM661547 373T2
GSM661548 373b1
Relations
BioProject PRJNA136113

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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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