WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.
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 lymph node-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 PaperFlick file available with the online Supplemental Data.
Nguyen
Don X
DX
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Chiang
Anne C
AC
Zhang
Xiang H-F
XH
Kim
Juliet Y
JY
Kris
Mark G
MG
Ladanyi
Marc
M
Gerald
William L
WL
Massagué
Joan
J
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism
C491257:HOXB9 protein, human; D018398:Homeodomain Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051820:TCF Transcription Factors; D051153:Wnt Proteins