Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression
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Hana Andrlová1, Justin Mastroianni1, Josef Madl2,3, Johannes S. Kern4, Wolfgang Melchinger1, Heide Dierbach1, Florian Wernet1, Marie Follo1, Kristin Technau-Hafsi4, Cristina Has4, Venugopal Rao Mittapalli4, Marco Idzko5, Ricarda Herr6, Tilman Brummer6, Hendrik Ungefroren7, Hauke Busch7,8,9,15, Melanie Boerries6,8,15, Andreas Narr10,11, Gabriele Ihorst12, Claire Vennin13, Annette Schmitt-Graeff14, Susana Minguet10,11, Paul Timpson13, Justus Duyster1, Frank Meiss4, Winfried Römer2,3 and Robert Zeiser1,3
1Department of Hematology and Oncology, University Medical Center, Faculty of Medicine, Freiburg, Germany
2Faculty of Biology, Albert Ludwigs University, Freiburg, Germany
3BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University Freiburg, Freiburg, Germany
4Department of Dermatology and Venereology, University Medical Center, Freiburg, Germany
5Department of Pneumology, University Medical Center, Freiburg, Germany
6Institut für Molekulare Medizin und Zellforschung, University Medical Center, Freiburg, Germany
7First Department of Medicine, University of Lübeck, Lübeck, Germany
8German Cancer Consortium (DKTK), Freiburg, Germany
9Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
10Department of Immunology, BIOSS Center for Biological Signaling Studies, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
11Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany
12Clinical Trials Unit, University Medical Center, Freiburg, Germany
13The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, Australia
14Department of Pathology, University Medical Center, Faculty of Medicine, Freiburg, Germany
15German Cancer Research Center (DKFZ), Heidelberg, Germany
Robert Zeiser, email: email@example.com
Keywords: biglycan, melanoma, microenvironment, tissue stiffness, integrin-β1
Received: October 04, 2016 Accepted: March 14, 2017 Published: April 17, 2017
Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies.
We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn-/- mice compared to Bgn+/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn-/- fibroblasts was reduced compared to melanoma invasion into Bgn-proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn-/- matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn+/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn-/- fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn-/- mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies.
This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.
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