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

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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:
CreatorsEmailORCIDORCID Put Code
Giebeler, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoenefuss, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landsberg, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuting, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauch, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zigrino, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
HEPATOCELLULAR-CARCINOMA; INCREASED EXPRESSION; CELL-MIGRATION; CANCER-CELL; IN-VITRO; TUMOR; INVASION; METALLOPROTEINASES; PROLIFERATION; ABNORMALITIESMultiple languages
Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22135

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