Mountain View
biomedical and healthCAre Data Discovery Index Ecosystem
help Advanced Search
Title: Suppression of Lung Adenocarcinoma Progression by Nkx2-1      
keywords:
Transcriptome or Gene expression
ID:
PRJNA136113
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. 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
accesstypes:
download
landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA136113
authentication:
none
authorization:
none
ID:
pmid:21471965
dateReleased:
01-27-2011
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • U01 CA084306-13/CA/NCI NIH HHS/United States

  • U01 CA084306-11/CA/NCI NIH HHS/United States

  • T32 HL007627/HL/NHLBI NIH HHS/United States

  • U01 CA084306-12/CA/NCI NIH HHS/United States

  • P30 CA014051/CA/NCI NIH HHS/United States

  • P30 CA014051-40/CA/NCI NIH HHS/United States

  • U01 CA084306/CA/NCI NIH HHS/United States

  • P30 CA014051-37/CA/NCI NIH HHS/United States

  • R01 CA109038/CA/NCI NIH HHS/United States

  • K99 CA151968/CA/NCI NIH HHS/United States

  • Howard Hughes Medical Institute/United States

  • P30 CA014051-36/CA/NCI NIH HHS/United States

  • P30 CA014051-39/CA/NCI NIH HHS/United States

  • P30 CA014051-38/CA/NCI NIH HHS/United States

  • K08 CA154784/CA/NCI NIH HHS/United States

Feedback?

If you are having problems using our tools, or if you would just like to send us some feedback, please post your questions on GitHub.