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.
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Stawowczyk
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Max D
authors.initials: MD
authors.lastname: Wellenstein
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Sharrell B
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of pharmacology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Yomtoubian
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Durrans
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pathology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA.
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA. Electronic address: dig2009@med.cornell.edu.
authors.forename: Dingcheng
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, 1300 York Avenue, 525 East 68th Street, NY, New York 10065, USA. Electronic address: vim2010@med.cornell.edu.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009367:Neoplasm Staging; D059748:Proteolysis; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D024042:Collagen Type I; D066257:Heparin-binding EGF-like Growth Factor; D066246:ErbB Receptors; D053511:Matrix Metalloproteinase 14