Abstract B39: Nkx2-1 down-regulation underlies lung adenocarcinoma progression towards malignancy

Metastasis leads to most cancer-related deaths, yet many of the molecular determinants and their mechanisms of action remain unknown. To uncover genetic programs that control the progression of lung adenocarcinoma towards malignancy, we developed and analyzed an autochthonous mouse model of this disease. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of genetically-engineered mice induces the development of widely metastatic lung adenocarcinoma. Using cell lines derived from primary tumors and metastases, we determined the genome-wide expression changes that embody a metastatic profile. Here we show that the NK-2 related homeobox transcription factor, Nkx2-1 (Ttf-1/Titf1), controls cancer progression and malignant phenotypes. Lung adenocarcinoma progression in our model is associated with loss of Nkx2-1 expression, consistent with the poor prognosis for patients with NKX2-1 negative lung adenocarcinoma. In cells derived from non-metastatic tumors, shRNA-mediated reduction of Nkx2-1 results in increased metastatic potential in vivo and phenotypic alterations in vitro consistent with increased metastatic ability. Interrogation of Nkx2-1 regulated genes and analysis of tumors at defined stages of development indicate that Nkx2-1 may constrain tumors by repressing embryonically-restricted transcriptional regulators and components of the extracellular matrix. Citation Information: Cancer Res 2009;69(23 Suppl):B39.