Journal
NATURE
Volume 527, Issue 7579, Pages 472-+Publisher
NATURE RESEARCH
DOI: 10.1038/nature15748
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Funding
- US Department of Defense CDMRP LCRP [LC110643]
- NIH [1 F31 CA186510-01]
- National Cancer Institute [U54 CA149196-05]
- WCMC Meyer Cancer Center Pilot Funding
- Neuberger Berman Foundation Lung Cancer Research Center
- Arthur and Myra Mahon Donor-Advised Fund
- Liz Claiborne and Art Ortenberg Foundation
- Douglas AMP
- Katherine McCormick Family Foundation
- R. AMP
- M. Goldberg Family Foundation
- P. AMP
- C. Collins Fund
- Eliot Stewart 'Wren' Fund
- William and Shelby Modell Family Foundation Trust
- Division of Thoracic Surgery
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The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.
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