Title | Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Fischer 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 |
Journal | Nature |
Volume | 527 |
Issue | 7579 |
Pagination | 472-6 |
Date Published | 2015 Nov 26 |
ISSN | 1476-4687 |
Keywords | Animals, 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 |
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. |
DOI | 10.1038/nature15748 |
Alternate Journal | Nature |
PubMed ID | 26560033 |
PubMed Central ID | PMC4662610 |
Grant List | 1 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 |