Despite the high prevalence and poor outcome of patients withmetastatic lung cancer the mechanisms of tumour progression andmetastasis remain largely uncharacterized. Here we modelledhuman lung adenocarcinoma, which frequently harbours activatingpoint mutations in KRAS and inactivation of the p53 pathway,using conditional alleles in mice. Lentiviral-mediated somaticactivation of oncogenic Kras and deletion of p53 in the lung epithelialcells of Kras[superscript LSL-G12D/+];p53[superscript flox/flox] mice initiates lung adenocarcinomadevelopment4. Although tumours are initiated synchronouslyby defined genetic alterations, only a subset becomes malignant,indicating that disease progression requires additional alterations.Identification of the lentiviral integration sites allowed us to distinguishmetastatic from non-metastatic tumours and determine thegene expression alterations that distinguish these tumour types.Cross-species analysis identified the NK2-related homeobox transcriptionfactor Nkx2-1 (also called Ttf-1 or Titf1) as a candidatesuppressor of malignant progression. In this mouse model, Nkx2-1negativity is pathognomonic of high-grade poorly differentiatedtumours. Gain- and loss-of-function experiments in cells derivedfrom metastatic and non-metastatic tumours demonstrated thatNkx2-1 controls tumour differentiation and limitsmetastatic potentialin vivo. Interrogation of Nkx2-1-regulated genes, analysis oftumours at defined developmental stages, and functional complementationexperiments indicate that Nkx2-1 constrains tumours inpart by repressing the embryonically restricted chromatin regulatorHmga2. Whereas focal amplification of NKX2-1 in a fraction ofhuman lung adenocarcinomas has focused attention on its oncogenicfunction, our data specifically link Nkx2-1 downregulationto loss of differentiation, enhanced tumour seeding ability andincreased metastatic proclivity. Thus, the oncogenic and suppressivefunctions ofNkx2-1 in the sametumour
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