title: Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance.
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.
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Kari R
authors.initials: KR
authors.lastname: Fischer
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Durrans
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Sharrell
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas 77030, USA.
authors.forename: Jianting
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas 77030, USA.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas 77030, USA.|Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, 77030 USA.
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: El Rayes
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25 Bongjeong-ro Cheonan-Si, Chungcheongnam-do 31151, South Korea.
authors.forename: Seongho
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.|Institute of Human Nutrition, Columbia University, New York, New York 10032, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Troeger
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.|Institute of Human Nutrition, Columbia University, New York, New York 10032, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.affiliation: Department of Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
authors.forename: Dingcheng
authors.initials: D
authors.lastname: Gao
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D058948:Cell Tracking; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000556:secondary*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015203:Reproducibility of Results
chemical_list: D018906:Antineoplastic Agents, Alkylating; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D003520:Cyclophosphamide