Universität zu Köln

Giebeler, N., Schoenefuss, A., Landsberg, J., Tuting, T., Mauch, C. and Zigrino, P. (2017). Deletion of ADAM-9 in HGF/CDK4 mice impairs melanoma development and metastasis. Oncogene, 36 (35). S. 5058 - 5068. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

Full text not available from this repository.

Abstract

ADAM-9 is a metalloproteinase expressed in peritumoral areas by invading melanoma cells and by adjacent peritumoral stromal cells; however, its function in stromal and melanoma cells is not fully understood. To address this question in vivo in a spontaneous melanoma model, we deleted ADAM-9 in mice carrying the hepatocyte growth factor (Hgf) transgene and knock-in mutation Cdk4(R24C/R24C), demonstrated to spontaneously develop melanoma. Spontaneous melanoma arose less frequently in ADAM-9-deleted mice than in controls. Similarly reduced tumor numbers (although with faster growth kinetics) were detected upon induction of melanoma with 7,12-dimethylbenz[a]anthracene (DMBA). However, more lesions were induced at early time points in the absence of ADAM-9. Increased initial and decreased late tumor numbers were paralleled by altered tumor cell proliferation, but not apoptosis or inflammation. Importantly, significantly reduced lung metastases were detected upon ADAM-9 deletion. Using in vitro assays to address this effect mechanistically, we detected reduced adhesion and transmigration of ADAM-9-silenced melanoma cells to/through the endothelium. This implies that ADAM-9 functionally and cell autonomously mediates extravasation of melanoma cells. In vitro and in vivo we demonstrated that the basement membrane (BM) component laminin beta 3-chain is a direct substrate of ADAM-9, thus contributing to destabilization and disruption of the BM barrier during invasion. In in vitro invasion assays using human melanoma cells and skin equivalents, depletion of ADAM-9 resulted in decreased invasion of the BM, which remained almost completely intact, as shown by continuous staining for laminin beta 3-chain. Importantly, supplying soluble ADAM-9 to the system reversed this effect. Taken together, our data show that melanoma derived ADAM-9 autonomously contributes to melanoma progression by modulating cell adhesion to the endothelium and altering BM integrity by proteolytically processing the laminin-beta 3 chain. This newly described process and ADAM-9 itself may represent potential targets for anti-tumor therapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Giebeler, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoenefuss, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Landsberg, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tuting, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zigrino, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-221353
DOI:	10.1038/onc.2017.162
Journal or Publication Title:	Oncogene
Volume:	36
Number:	35
Page Range:	S. 5058 - 5068
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATOCELLULAR-CARCINOMA; INCREASED EXPRESSION; CELL-MIGRATION; CANCER-CELL; IN-VITRO; TUMOR; INVASION; METALLOPROTEINASES; PROLIFERATION; ABNORMALITIES Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22135