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Control of Alveolar Differentiation by the Lineage Transcription Factors GATA6 and HOPX Inhibits Lung Adenocarcinoma Metastasis (1)教程.pdf

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Cancer Cell Article Control of Alveolar Differentiation by the Lineage Transcription Factors GATA6 and HOPX Inhibits Lung Adenocarcinoma Metastasis William K.C. Cheung,1 Minghui Zhao,1 Zongzhi Liu,1 Laura E. Stevens,1 Paul D. Cao,1 Justin E. Fang,3 Thomas F. Westbrook,3 and Don X. Nguyen1,2,* 1Department of Pathology 2Yale Cancer Center Yale University School of Medicine, New Haven, CT 06510, USA 3Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA *Correspondence: don.nguyen@ /10.1016/j.ccr.2013.04.009 SUMMARY Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell sur- vival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype. INTRODUCTION Multipotent cells from the primary lung buds differentiate into epithelial bronchiolar or alveolar progenitors of the proximal and Aberrant activation of cell-lineage-restricted pathways is distal airway, respectively (Morrisey and Hogan, 2010). In post- required for oncogenic transformation in certain malignancies natal lungs, these cells may arise from regional stem cells in (Garraway and Selle
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