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Updated: May 19, 2026
In Vivo Imaging to Measure Spontaneous Lung Metastasis of Orthotopically-injected Breast Tumor Cells
Published on: June 23, 2022
The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites
Hua Gao1, Goutam Chakraborty, Ai Ping Lee-Lim
1Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. f-giancotti@ski.mskcc.org
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.
Insights
Coco, a TGF-β antagonist, reactivates dormant breast cancer cells in the lung by blocking BMP signals. This discovery sheds light on organ-specific metastatic relapse and cancer stem cell traits.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Metastatic dormancy and reactivation mechanisms remain poorly understood.
- Understanding these processes is crucial for treating cancer spread.
Purpose of the Study:
- To identify factors that induce dormant breast cancer cell reactivation.
- To elucidate the role of specific signaling pathways in metastatic relapse.
Main Methods:
- Conducted a gain-of-function cDNA screen in breast cancer cells.
- Performed mechanistic studies involving Coco, TGF-β, and BMP ligands.
- Analyzed gene expression signatures and patient data.
- Utilized mouse models of metastasis.
Main Results:
- Coco, a TGF-β antagonist, reactivates dormant breast cancer cells in the lung.
- Coco functions by blocking lung-derived Bone Morphogenetic Protein (BMP) ligands.
- Coco promotes cancer stem cell traits, while BMP signaling suppresses them.
- A Coco-induced gene signature correlates with lung, but not bone or brain, metastatic relapse.
- Mouse models indicate BMP-deficient niches in bone and brain.
Conclusions:
- Organ-specific antimetastatic signals, like BMP in the lung, must be overcome by metastasis-initiating cells for reactivation.
- Coco's mechanism highlights a novel pathway for overcoming dormancy.
- Findings provide insights into targeted therapies for preventing metastatic relapse.
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