Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance

Kari R. Fischer, Anna Durrans, Sharrell Lee, Jianting Sheng, Fuhai Li, Stephen T. C. Wong, Hyejin Choi, Tina El Rayes, Seongho Ryu, Juliane Troeger, Robert F. Schwabe, Linda T. Vahdat, Nasser K. Altorki, Vivek Mittal () and Dingcheng Gao ()
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Kari R. Fischer: Weill Cornell Medical College of Cornell University
Anna Durrans: Weill Cornell Medical College of Cornell University
Sharrell Lee: Weill Cornell Medical College of Cornell University
Jianting Sheng: Houston Methodist Research Institute, Houston Methodist Hospital
Fuhai Li: Houston Methodist Research Institute, Houston Methodist Hospital
Stephen T. C. Wong: Houston Methodist Research Institute, Houston Methodist Hospital
Hyejin Choi: Weill Cornell Medical College of Cornell University
Tina El Rayes: Weill Cornell Medical College of Cornell University
Seongho Ryu: Weill Cornell Medical College of Cornell University
Juliane Troeger: Columbia University, College of Physicians and Surgeons
Robert F. Schwabe: Columbia University, College of Physicians and Surgeons
Linda T. Vahdat: Weill Cornell Medical College of Cornell University
Nasser K. Altorki: Weill Cornell Medical College of Cornell University
Vivek Mittal: Weill Cornell Medical College of Cornell University
Dingcheng Gao: Weill Cornell Medical College of Cornell University

Nature, 2015, vol. 527, issue 7579, 472-476

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/nature15748

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