Research Papers:

Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression

Hana Andrlová _, Justin Mastroianni, Josef Madl, Johannes S. Kern, Wolfgang Melchinger, Heide Dierbach, Florian Wernet, Marie Follo, Kristin Technau-Hafsi, Cristina Has, Venugopal Rao Mittapalli, Marco Idzko, Ricarda Herr, Tilman Brummer, Hendrik Ungefroren, Hauke Busch, Melanie Boerries, Andreas Narr, Gabriele Ihorst, Claire Vennin, Annette Schmitt-Graeff, Susana Minguet, Paul Timpson, Justus Duyster, Frank Meiss, Winfried Römer and Robert Zeiser

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Oncotarget. 2017; 8:42901-42916. https://doi.org/10.18632/oncotarget.17160

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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

Correspondence to:

Robert Zeiser, email: [email protected]

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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