The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites |
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Authors: | Hua Gao Goutam Chakraborty Ai Ping Lee-Lim Qianxing Mo Markus Decker Alin Vonica Ronglai Shen Edi Brogi Ali H Brivanlou Filippo G Giancotti |
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Affiliation: | 1 Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 2 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 4 Laboratory of Molecular Embryology, The Rockefeller University, New York, NY 10065, USA |
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Abstract: | The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation. |
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