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

Research output: Contribution to journalArticle

Kari R Fischer, Anna Durrans, Sharrell Lee, Jianting Sheng, Fuhai Li, Stephen T C Wong, Hyejin Choi, Tina El Rayes, Seongho Ryu, Juliane Troeger, Robert F Schwabe, Linda T Vahdat, Nasser K Altorki, Vivek Mittal, Dingcheng Gao

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.

Original languageEnglish (US)
Pages (from-to)472-6
Number of pages5
JournalNature
Volume527
Issue number7579
DOIs
StatePublished - Nov 26 2015

PMID: 26560033

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Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. / Fischer, Kari R; Durrans, Anna; Lee, Sharrell; Sheng, Jianting; Li, Fuhai; Wong, Stephen T C; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Troeger, Juliane; Schwabe, Robert F; Vahdat, Linda T; Altorki, Nasser K; Mittal, Vivek; Gao, Dingcheng.

In: Nature, Vol. 527, No. 7579, 26.11.2015, p. 472-6.

Research output: Contribution to journalArticle

Harvard

Fischer, KR, Durrans, A, Lee, S, Sheng, J, Li, F, Wong, STC, Choi, H, El Rayes, T, Ryu, S, Troeger, J, Schwabe, RF, Vahdat, LT, Altorki, NK, Mittal, V & Gao, D 2015, 'Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance' Nature, vol. 527, no. 7579, pp. 472-6. https://doi.org/10.1038/nature15748

APA

Fischer, K. R., Durrans, A., Lee, S., Sheng, J., Li, F., Wong, S. T. C., ... Gao, D. (2015). Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature, 527(7579), 472-6. https://doi.org/10.1038/nature15748

Vancouver

Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015 Nov 26;527(7579):472-6. https://doi.org/10.1038/nature15748

Author

Fischer, Kari R ; Durrans, Anna ; Lee, Sharrell ; Sheng, Jianting ; Li, Fuhai ; Wong, Stephen T C ; Choi, Hyejin ; El Rayes, Tina ; Ryu, Seongho ; Troeger, Juliane ; Schwabe, Robert F ; Vahdat, Linda T ; Altorki, Nasser K ; Mittal, Vivek ; Gao, Dingcheng. / Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. In: Nature. 2015 ; Vol. 527, No. 7579. pp. 472-6.

BibTeX

@article{153fc083afac4fa7b8d12a0afff9b1ec,
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.",
author = "Fischer, {Kari R} and Anna Durrans and Sharrell Lee and Jianting Sheng and Fuhai Li and Wong, {Stephen T C} and Hyejin Choi and {El Rayes}, Tina and Seongho Ryu and Juliane Troeger and Schwabe, {Robert F} and Vahdat, {Linda T} and Altorki, {Nasser K} and Vivek Mittal and Dingcheng Gao",
year = "2015",
month = "11",
day = "26",
doi = "10.1038/nature15748",
language = "English (US)",
volume = "527",
pages = "472--6",
journal = "Nature",
issn = "0028-0836",
number = "7579",

}

RIS

TY - JOUR

T1 - Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance

AU - Fischer, Kari R

AU - Durrans, Anna

AU - Lee, Sharrell

AU - Sheng, Jianting

AU - Li, Fuhai

AU - Wong, Stephen T C

AU - Choi, Hyejin

AU - El Rayes, Tina

AU - Ryu, Seongho

AU - Troeger, Juliane

AU - Schwabe, Robert F

AU - Vahdat, Linda T

AU - Altorki, Nasser K

AU - Mittal, Vivek

AU - Gao, Dingcheng

PY - 2015/11/26

Y1 - 2015/11/26

N2 - 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.

AB - 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.

U2 - 10.1038/nature15748

DO - 10.1038/nature15748

M3 - Article

VL - 527

SP - 472

EP - 476

JO - Nature

T2 - Nature

JF - Nature

SN - 0028-0836

IS - 7579

ER -

ID: 18762962