A Secreted BMP Inhibitor Mediates Metastatic Colonization in the Lung

Cancer cells that disseminate to distant organs must also overcome inhibitory signals within these foreign microenvironments to proliferate and form metastatic outgrowths. Metastatic colonization is thought to be mediated by cancer stem cells, which possess self-renewal ability and are associated with a mesenchymal phenotype, but the molecular mechanisms that trigger their exit from dormancy are unknown. Gao and colleagues used a gain-of-function screen in mammary carcinoma cell lines with different metastatic potentials and identified Coco, a secreted inhibitor of the TGF-β ligand bone morphogenetic protein (BMP), as an important regulator of metastasis-initiating cells in the lung. Expression of Coco enabled nonmetastatic cells to form lung outgrowths, whereas depletion of Coco in metastatic cells prevented lung colonization, indicating that Coco is essential for this step of metastasis. In support of this notion, Coco was necessary and sufficient to stimulate the proliferation of quiescent, solitary tumor cells in the lung. This effect was mediated via inhibition of lung-derived BMP signaling by Coco in metastasis-initiating cells; suppression of BMP activity resulted in reactivation of dormant cells, as was the case with Coco, and rescued the lung-colonizing capability of metastatic cells lacking Coco expression. Furthermore, Coco promoted cancer cell self-renewal, induced the expression of stem cell transcription factors, and augmented primary tumor initiation, suggesting that Coco contributes to colonization by enhancing stem cell characteristics, whereas BMP exerted the opposite effects. Importantly, a Coco-dependent gene expression signature, in particular the genes NDRG1 and KIAA1199, was strongly associated with metastatic relapse to the lung but not metastasis to the bone or brain, which did not express high levels of BMP. These results delineate a mechanism regulating tissue-specific metastatic colonization and suggest that targeting of factors such as Coco may limit metastatic spread.

Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 2012;150:764–79.

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