WNT/TCF Signaling through LEF1 and HOXB9 Mediates Lung Adenocarcinoma Metastasis

被引:531
作者
Nguyen, Don X. [1 ]
Chiang, Anne C. [2 ]
Zhang, Xiang H. -F. [1 ]
Kim, Juliet Y. [1 ]
Kris, Mark G. [2 ,5 ]
Ladanyi, Marc [3 ,4 ]
Gerald, William L. [3 ,4 ]
Massague, Joan [1 ,6 ]
机构
[1] Cornell Univ, Canc Biol & Genet Program, Ithaca, NY 14853 USA
[2] Cornell Univ, Dept Med, Ithaca, NY 14853 USA
[3] Cornell Univ, Dept Pathol, Ithaca, NY 14853 USA
[4] Cornell Univ, Human Oncol & Pathogenesis Program, Ithaca, NY 14853 USA
[5] Cornell Univ, Weill Med Coll, Ithaca, NY 14853 USA
[6] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA
基金
美国国家卫生研究院;
关键词
GENE-EXPRESSION; BETA-CATENIN; BRAIN METASTASES; STEM-CELLS; CANCER; WNT; RECURRENCE; ACTIVATION; MUTATIONS; PATHWAY;
D O I
10.1016/j.cell.2009.04.030
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymphnode-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus, a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain. For a video summary of this article, see the Paper Flick file available with the online Supplemental Data.
引用
收藏
页码:51 / 62
页数:12
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