Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating...

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Autores principales:	Elke Pach, Maike Kümper, Julia E. Fromme, Jan Zamek, Fabian Metzen, Manuel Koch, Cornelia Mauch, Paola Zigrino
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	MMP14 proteases melanoma collagen extracellular matrix Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0c577ce28b124de9b938137cc3546ba9
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spelling	oai:doaj.org-article:0c577ce28b124de9b938137cc3546ba92021-11-25T17:54:57ZExtracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth10.3390/ijms2222122761422-00671661-6596https://doaj.org/article/0c577ce28b124de9b938137cc3546ba92021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12276https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast’s matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast’s deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14.Elke PachMaike KümperJulia E. FrommeJan ZamekFabian MetzenManuel KochCornelia MauchPaola ZigrinoMDPI AGarticleMMP14proteasesmelanomacollagenextracellular matrixBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12276, p 12276 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MMP14 proteases melanoma collagen extracellular matrix Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	MMP14 proteases melanoma collagen extracellular matrix Biology (General) QH301-705.5 Chemistry QD1-999 Elke Pach Maike Kümper Julia E. Fromme Jan Zamek Fabian Metzen Manuel Koch Cornelia Mauch Paola Zigrino Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth
description	Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast’s matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast’s deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14.
format	article
author	Elke Pach Maike Kümper Julia E. Fromme Jan Zamek Fabian Metzen Manuel Koch Cornelia Mauch Paola Zigrino
author_facet	Elke Pach Maike Kümper Julia E. Fromme Jan Zamek Fabian Metzen Manuel Koch Cornelia Mauch Paola Zigrino
author_sort	Elke Pach
title	Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth
title_short	Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth
title_full	Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth
title_fullStr	Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth
title_full_unstemmed	Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth
title_sort	extracellular matrix remodeling by fibroblast-mmp14 regulates melanoma growth
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0c577ce28b124de9b938137cc3546ba9
work_keys_str_mv	AT elkepach extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT maikekumper extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT juliaefromme extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT janzamek extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT fabianmetzen extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT manuelkoch extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT corneliamauch extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth AT paolazigrino extracellularmatrixremodelingbyfibroblastmmp14regulatesmelanomagrowth
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Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

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