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

TitleEpithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance.
Publication TypeJournal Article
Year of Publication2015
AuthorsFischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC, Choi H, Rayes TEl, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, Mittal V, Gao D
Date Published2015 Nov 26
KeywordsAnimals, Antineoplastic Agents, Alkylating, Apoptosis, Cell Lineage, Cell Proliferation, Cell Tracking, Cyclophosphamide, Disease Models, Animal, Disease Progression, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Female, Lung Neoplasms, Male, Mammary Neoplasms, Experimental, Mice, MicroRNAs, Neoplasm Metastasis, Reproducibility of Results

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.

Alternate JournalNature
PubMed ID26560033
PubMed Central IDPMC4662610
Grant List1 F31 CA186510-01 / CA / NCI NIH HHS / United States
F31 CA186510 / CA / NCI NIH HHS / United States
R01 CA135417 / CA / NCI NIH HHS / United States
U01 CA188388 / CA / NCI NIH HHS / United States
U54 CA149196-05 / CA / NCI NIH HHS / United States