Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor

Research output: Contribution to journalArticle

Marcin Stawowczyk, Max D. Wellenstein, Sharrell B. Lee, Shira Yomtoubian, Anna Durrans, Hyejin Choi, Navneet Narula, Nasser K. Altorki, Dingcheng Gao, Vivek Mittal

Molecularly targeted therapies benefit approximately 15–20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53−/− mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF-like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis.

Original languageEnglish (US)
Pages (from-to)55-64
Number of pages10
JournalNeoplasia (United States)
Volume19
Issue number2
DOIs
StatePublished - 2017

PMID: 28013056

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Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor. / Stawowczyk, Marcin; Wellenstein, Max D.; Lee, Sharrell B.; Yomtoubian, Shira; Durrans, Anna; Choi, Hyejin; Narula, Navneet; Altorki, Nasser K.; Gao, Dingcheng; Mittal, Vivek.

In: Neoplasia (United States), Vol. 19, No. 2, 2017, p. 55-64.

Research output: Contribution to journalArticle

Harvard

Stawowczyk, M, Wellenstein, MD, Lee, SB, Yomtoubian, S, Durrans, A, Choi, H, Narula, N, Altorki, NK, Gao, D & Mittal, V 2017, 'Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor' Neoplasia (United States), vol. 19, no. 2, pp. 55-64. https://doi.org/10.1016/j.neo.2016.11.005

APA

Stawowczyk, M., Wellenstein, M. D., Lee, S. B., Yomtoubian, S., Durrans, A., Choi, H., ... Mittal, V. (2017). Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor. Neoplasia (United States), 19(2), 55-64. https://doi.org/10.1016/j.neo.2016.11.005

Vancouver

Stawowczyk M, Wellenstein MD, Lee SB, Yomtoubian S, Durrans A, Choi H et al. Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor. Neoplasia (United States). 2017;19(2):55-64. https://doi.org/10.1016/j.neo.2016.11.005

Author

Stawowczyk, Marcin ; Wellenstein, Max D. ; Lee, Sharrell B. ; Yomtoubian, Shira ; Durrans, Anna ; Choi, Hyejin ; Narula, Navneet ; Altorki, Nasser K. ; Gao, Dingcheng ; Mittal, Vivek. / Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor. In: Neoplasia (United States). 2017 ; Vol. 19, No. 2. pp. 55-64.

BibTeX

@article{92fa4958b0a04a7e891da76a2f75b2ae,
title = "Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor",
abstract = "Molecularly targeted therapies benefit approximately 15–20{\%} of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53−/− mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF-like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis.",
author = "Marcin Stawowczyk and Wellenstein, {Max D.} and Lee, {Sharrell B.} and Shira Yomtoubian and Anna Durrans and Hyejin Choi and Navneet Narula and Altorki, {Nasser K.} and Dingcheng Gao and Vivek Mittal",
year = "2017",
doi = "10.1016/j.neo.2016.11.005",
language = "English (US)",
volume = "19",
pages = "55--64",
journal = "Neoplasia (United States)",
issn = "1522-8002",
publisher = "Elsevier",
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RIS

TY - JOUR

T1 - Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor

AU - Stawowczyk, Marcin

AU - Wellenstein, Max D.

AU - Lee, Sharrell B.

AU - Yomtoubian, Shira

AU - Durrans, Anna

AU - Choi, Hyejin

AU - Narula, Navneet

AU - Altorki, Nasser K.

AU - Gao, Dingcheng

AU - Mittal, Vivek

PY - 2017

Y1 - 2017

N2 - Molecularly targeted therapies benefit approximately 15–20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53−/− mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF-like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis.

AB - Molecularly targeted therapies benefit approximately 15–20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53−/− mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF-like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis.

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U2 - 10.1016/j.neo.2016.11.005

DO - 10.1016/j.neo.2016.11.005

M3 - Article

VL - 19

SP - 55

EP - 64

JO - Neoplasia (United States)

T2 - Neoplasia (United States)

JF - Neoplasia (United States)

SN - 1522-8002

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ER -

ID: 29725967