The ability of a cancer to spread to distant sites through metastasis is one of its most ominous properties; unlike localized disease, metastatic disease can only rarely be cured. Different forms of cancer show different propensities for metastasis; lung adenocarcinoma—which has a high mortality rate—can be found in multiple organs within months of its diagnosis. Nguyen et al. analyzed a cohort of 107 primary human lung adenocarcinomas and found that a gene expression signature denoting activation of TCF4 (T cell factor 4, a transcription factor that is an effector of the WNT signaling pathway) was associated with an increased rate of recurrence in multiple organs. Two highly metastatic sublines of human lung adenocarcinoma cell lines established from lymph nodes (selected through repeated rounds of brain metastasis in immunodeficient mice, these sublines showed increased capacity for bone as well as brain metastasis) showed increased basal TCF transcriptional activity relative to their respective parental lines, as well as an increase in Wnt3a-stimulated activity. Expression of dominant-negative TCFs inhibited metastatic activity of these sublines in immunodeficient mice, without substantially affecting their growth in lung. The expression patterns of two WNT target genes, LEF1 and HOXB9, were consistent with constitutive hyperactivation of WNT signaling in one metastatic subline and enhanced sensitivity to Wnt3a stimulation in the other. Their knockdown with RNAi decreased the ability of both sublines to form brain and bone metastases in immunodeficient mice, whereas their overexpression promoted metastatic activity of the parental lines. Ex vivo analysis implicated LEF1 in growth of colonies in Matrigel, and both LEF1 and HOXB9 in invasion through Matrigel toward astrocyte-conditioned medium. The authors thus conclude that increased activation of the WNT/TCF signaling pathway enhances the ability of lung adenocarcinoma to metastasize to brain and bone.
D. X. Nguyen, A. C. Chiang, X. H.-F. Zhang, J. Y. Kim, M. G. Kris, M. Ladanyi, W. L. Gerald, J. Massagué, WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138, 51–62 (2009). [PubMed]