Universität zu Köln

Pach, Elke ORCID: 0000-0001-6409-6134, Brinckmann, Juergen, Ruebsam, Matthias, Kuemper, Maike, Mauch, Cornelia and Zigrino, Paola ORCID: 0000-0002-7470-0064 (2021). Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth. Cancers, 13 (8). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Matrix metalloproteinases (MMPs) were considered as targets for the treatment of various cancers. However, initial trials using broad inhibitors to MMPs have failed, partly attributed to the contrasting functions of these proteases acting as tumor promoters and suppressors, among other reasons. Our data now suggest that specific inhibition of MMP14 might represent a more specific approach, as loss of this protease in fibroblasts resulted in reduced growth of grafted melanomas. Here, we found that deletion of MMP14 in fibroblasts generates a matrix-rich environment that reduces tumor vascularization and melanoma cell proliferation. In in vitro and ex vivo assays, we showed that the latter is mediated by stiffening of the tissue due to collagen accumulation. Additionally, in vivo, we show that independently of MMP14 deletion, a collagen-rich stiff matrix inhibits the growth of melanomas. Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14(Sf-/-)) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired proteolysis. Here, we show that melanoma growth in these mouse fibrotic dermal samples was decreased, paralleled by reduced tumor cell proliferation and vessel density. Using atomic force microscopy, we found increased peritumoral matrix stiffness of early but not late melanomas in the absence of fibroblast-derived MMP14. However, total collagen levels were increased at late melanoma stages in MMP14(Sf-/-) mice compared to controls. In ex vivo invasion assays, melanoma cells formed smaller tumor islands in MMP14(Sf-/-) skin, indicating that MMP14-dependent matrix accumulation regulates tumor growth. In line with these data, in vitro melanoma cell growth was inhibited in high collagen 3D spheroids or stiff substrates. Most importantly, in vivo induction of fibrosis using bleomycin reduced melanoma tumor growth. In summary, we show that MMP14 expression in stromal fibroblasts regulates melanoma tumor progression by modifying the peritumoral matrix and point to collagen accumulation as a negative regulator of melanoma.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pach, Elke UNSPECIFIED orcid.org/0000-0001-6409-6134 UNSPECIFIED Brinckmann, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruebsam, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuemper, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Zigrino, Paola UNSPECIFIED orcid.org/0000-0002-7470-0064 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-579959
DOI:	10.3390/cancers13081984
Journal or Publication Title:	Cancers
Volume:	13
Number:	8
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57995