Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance
Open accessAbstract
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.
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Carcinoma cells undergoing EMT tend to be more resistant to chemotherapy.
“EMT also correlates with increased resistance of carcinoma cells to chemotherapies149–152.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [151]
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- Authors
- Fischer, K. R., Durrans, A., Lee, S., Sheng, J., Li, F., Wong, S. T. C., Choi, H., El Rayes, T., Ryu, S., Troeger, J., Schwabe, R. F., Vahdat, L. T., Altorki, N. K., Mittal, V., & Gao, D.
- Affiliations
- Cornell University (US)
- Houston Methodist (US)
- Columbia University (US)
- Corresponding author
- Mittal, Vivek
- Gao, Dingcheng
- ORCID
- Venue
- Nature
- Published
- 2015-11-11
- Volume
- 527
- Issue
- 7579
- Pages
- 472-476
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4662610
- OpenAlex
- W2150322923
- Cited by
- 1,791
- References
- 38
- Citations by year
- 2026: 53 · 2025: 78 · 2024: 101 · 2023: 138 · 2022: 151 · 2021: 182 · 2020: 217 · 2019: 222 · 2018: 195 · 2017: 262 · 2016: 181 · 2015: 5 · 2014: 3
- FWCI
- 93.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5f31ca186510-02)
- National Cancer Institute (F31 CA186510, U01CA188388, U54CA149196, R01CA135417, 1 F31 CA186510-01)
- National Institute of General Medical Sciences (T32GM008539)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- epithelial-mesenchymal transition, chemoresistance, miR-200 family, lineage tracing, cyclophosphamide, Twist, snails, tumor recurrence, apoptosis, metastasis origin, pancreatic ductal adenocarcinoma, lung metastasis
- MeSH terms
- Animals, Cyclophosphamide, Disease Models, Animal, Female, Lung Neoplasms, Male, Mammary Neoplasms, Experimental, Neoplasm Metastasis, Reproducibility of Results, Apoptosis, Disease Progression, Antineoplastic Agents, Alkylating, Drug Resistance, Neoplasm, Cell Lineage, MicroRNAs, Cell Proliferation, Mice, Epithelial-Mesenchymal Transition, Cell Tracking
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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