Format

Send to

Choose Destination
Nature. 2015 Nov 26;527(7579):472-6. doi: 10.1038/nature15748. Epub 2015 Nov 11.

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

Fischer KR1,2,3,4, Durrans A1,2,3, Lee S1,2,3, Sheng J5, Li F5, Wong ST5,6, Choi H1,2,3,4, El Rayes T1,2,3,4, Ryu S1,3,7, Troeger J8,9, Schwabe RF8,9, Vahdat LT10, Altorki NK1,3, Mittal V1,2,3, Gao D1,2,3.

Author information

1
Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
2
Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
3
Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
4
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
5
Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas 77030, USA.
6
Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, 77030 USA.
7
Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25 Bongjeong-ro Cheonan-Si, Chungcheongnam-do 31151, South Korea.
8
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
9
Institute of Human Nutrition, Columbia University, New York, New York 10032, USA.
10
Department of Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.

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.

PMID:
26560033
PMCID:
PMC4662610
DOI:
10.1038/nature15748
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center