In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors

Research output: Contribution to journalArticle

Zhen Zhao, Xiaoping Zhu, Kemi Cui, James Mancuso, Richard Federley, Kari Fischer, Gao Jun Teng, Vivek Mittal, Dingcheng Gao, Hong Zhao, Stephen T. Wong

The activation of the epithelial-to-mesenchymal transition (EMT) program is a critical step in cancer progression and metastasis, but visualization of this process at the single-cell level, especially in vivo, remains challenging. We established an in vivo approach to track the fate of tumor cells based on a novel EMTdriven fluorescent color switching breast cancer mouse model and intravital two-photon laser scanning microscopy. Specifically, the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple transgenic mouse model was used to monitor the conversion of RFP-positive epithelial cells to GFP-positive mesenchymal cells in mammary tumors under the control of the Fsp1 (ATL1) promoter, a gatekeeper of EMT initiation. RFP-positive cells were isolated from the tumors, sorted, and transplanted into mammary fat pads of SCID mice to monitor EMT during breast tumor formation. We found that the conversion from RFP- to GFP-positive and spindleshaped cells was a gradual process, and that GFP-positive cells preferentially localized close to blood vessels, independent of tumor size. Furthermore, cells undergoing EMT expressed high levels of the HGF receptor, c-Met, and treatment of RFP-positive cells with the c-Met inhibitor, cabozantinib, suppressed the RFP-to-GFP conversion in vitro. Moreover, administration of cabozantinib to mice with palpable RFP-positive tumors resulted in a silent EMT phenotype whereby GFP-positive cells exhibited reduced motility, leading to suppressed tumor growth. In conclusion, our imaging technique provides a novel opportunity for visualizing tumor EMT at the single-cell level and may help to reveal the intricacies underlying tumor dynamics and treatment responses.

Original languageEnglish (US)
Pages (from-to)2094-2104
Number of pages11
JournalCancer Research
Volume76
Issue number8
DOIs
StatePublished - Apr 15 2016

PMID: 26893478

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In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors. / Zhao, Zhen; Zhu, Xiaoping; Cui, Kemi; Mancuso, James; Federley, Richard; Fischer, Kari; Teng, Gao Jun; Mittal, Vivek; Gao, Dingcheng; Zhao, Hong; Wong, Stephen T.

In: Cancer Research, Vol. 76, No. 8, 15.04.2016, p. 2094-2104.

Research output: Contribution to journalArticle

Harvard

Zhao, Z, Zhu, X, Cui, K, Mancuso, J, Federley, R, Fischer, K, Teng, GJ, Mittal, V, Gao, D, Zhao, H & Wong, ST 2016, 'In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors' Cancer Research, vol. 76, no. 8, pp. 2094-2104. https://doi.org/10.1158/0008-5472.CAN-15-2662

APA

Zhao, Z., Zhu, X., Cui, K., Mancuso, J., Federley, R., Fischer, K., ... Wong, S. T. (2016). In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors. Cancer Research, 76(8), 2094-2104. https://doi.org/10.1158/0008-5472.CAN-15-2662

Vancouver

Zhao Z, Zhu X, Cui K, Mancuso J, Federley R, Fischer K et al. In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors. Cancer Research. 2016 Apr 15;76(8):2094-2104. https://doi.org/10.1158/0008-5472.CAN-15-2662

Author

Zhao, Zhen ; Zhu, Xiaoping ; Cui, Kemi ; Mancuso, James ; Federley, Richard ; Fischer, Kari ; Teng, Gao Jun ; Mittal, Vivek ; Gao, Dingcheng ; Zhao, Hong ; Wong, Stephen T. / In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors. In: Cancer Research. 2016 ; Vol. 76, No. 8. pp. 2094-2104.

BibTeX

@article{4bde9f7a6d9e429c8dcd161b1a64d20b,
title = "In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors",
abstract = "The activation of the epithelial-to-mesenchymal transition (EMT) program is a critical step in cancer progression and metastasis, but visualization of this process at the single-cell level, especially in vivo, remains challenging. We established an in vivo approach to track the fate of tumor cells based on a novel EMTdriven fluorescent color switching breast cancer mouse model and intravital two-photon laser scanning microscopy. Specifically, the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple transgenic mouse model was used to monitor the conversion of RFP-positive epithelial cells to GFP-positive mesenchymal cells in mammary tumors under the control of the Fsp1 (ATL1) promoter, a gatekeeper of EMT initiation. RFP-positive cells were isolated from the tumors, sorted, and transplanted into mammary fat pads of SCID mice to monitor EMT during breast tumor formation. We found that the conversion from RFP- to GFP-positive and spindleshaped cells was a gradual process, and that GFP-positive cells preferentially localized close to blood vessels, independent of tumor size. Furthermore, cells undergoing EMT expressed high levels of the HGF receptor, c-Met, and treatment of RFP-positive cells with the c-Met inhibitor, cabozantinib, suppressed the RFP-to-GFP conversion in vitro. Moreover, administration of cabozantinib to mice with palpable RFP-positive tumors resulted in a silent EMT phenotype whereby GFP-positive cells exhibited reduced motility, leading to suppressed tumor growth. In conclusion, our imaging technique provides a novel opportunity for visualizing tumor EMT at the single-cell level and may help to reveal the intricacies underlying tumor dynamics and treatment responses.",
author = "Zhen Zhao and Xiaoping Zhu and Kemi Cui and James Mancuso and Richard Federley and Kari Fischer and Teng, {Gao Jun} and Vivek Mittal and Dingcheng Gao and Hong Zhao and Wong, {Stephen T.}",
year = "2016",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-15-2662",
language = "English (US)",
volume = "76",
pages = "2094--2104",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

RIS

TY - JOUR

T1 - In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors

AU - Zhao, Zhen

AU - Zhu, Xiaoping

AU - Cui, Kemi

AU - Mancuso, James

AU - Federley, Richard

AU - Fischer, Kari

AU - Teng, Gao Jun

AU - Mittal, Vivek

AU - Gao, Dingcheng

AU - Zhao, Hong

AU - Wong, Stephen T.

PY - 2016/4/15

Y1 - 2016/4/15

N2 - The activation of the epithelial-to-mesenchymal transition (EMT) program is a critical step in cancer progression and metastasis, but visualization of this process at the single-cell level, especially in vivo, remains challenging. We established an in vivo approach to track the fate of tumor cells based on a novel EMTdriven fluorescent color switching breast cancer mouse model and intravital two-photon laser scanning microscopy. Specifically, the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple transgenic mouse model was used to monitor the conversion of RFP-positive epithelial cells to GFP-positive mesenchymal cells in mammary tumors under the control of the Fsp1 (ATL1) promoter, a gatekeeper of EMT initiation. RFP-positive cells were isolated from the tumors, sorted, and transplanted into mammary fat pads of SCID mice to monitor EMT during breast tumor formation. We found that the conversion from RFP- to GFP-positive and spindleshaped cells was a gradual process, and that GFP-positive cells preferentially localized close to blood vessels, independent of tumor size. Furthermore, cells undergoing EMT expressed high levels of the HGF receptor, c-Met, and treatment of RFP-positive cells with the c-Met inhibitor, cabozantinib, suppressed the RFP-to-GFP conversion in vitro. Moreover, administration of cabozantinib to mice with palpable RFP-positive tumors resulted in a silent EMT phenotype whereby GFP-positive cells exhibited reduced motility, leading to suppressed tumor growth. In conclusion, our imaging technique provides a novel opportunity for visualizing tumor EMT at the single-cell level and may help to reveal the intricacies underlying tumor dynamics and treatment responses.

AB - The activation of the epithelial-to-mesenchymal transition (EMT) program is a critical step in cancer progression and metastasis, but visualization of this process at the single-cell level, especially in vivo, remains challenging. We established an in vivo approach to track the fate of tumor cells based on a novel EMTdriven fluorescent color switching breast cancer mouse model and intravital two-photon laser scanning microscopy. Specifically, the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple transgenic mouse model was used to monitor the conversion of RFP-positive epithelial cells to GFP-positive mesenchymal cells in mammary tumors under the control of the Fsp1 (ATL1) promoter, a gatekeeper of EMT initiation. RFP-positive cells were isolated from the tumors, sorted, and transplanted into mammary fat pads of SCID mice to monitor EMT during breast tumor formation. We found that the conversion from RFP- to GFP-positive and spindleshaped cells was a gradual process, and that GFP-positive cells preferentially localized close to blood vessels, independent of tumor size. Furthermore, cells undergoing EMT expressed high levels of the HGF receptor, c-Met, and treatment of RFP-positive cells with the c-Met inhibitor, cabozantinib, suppressed the RFP-to-GFP conversion in vitro. Moreover, administration of cabozantinib to mice with palpable RFP-positive tumors resulted in a silent EMT phenotype whereby GFP-positive cells exhibited reduced motility, leading to suppressed tumor growth. In conclusion, our imaging technique provides a novel opportunity for visualizing tumor EMT at the single-cell level and may help to reveal the intricacies underlying tumor dynamics and treatment responses.

UR - http://www.scopus.com/inward/record.url?scp=84964560527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964560527&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-2662

DO - 10.1158/0008-5472.CAN-15-2662

M3 - Article

VL - 76

SP - 2094

EP - 2104

JO - Cancer Research

T2 - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 8

ER -

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ID: 20973458