Over the last few years, it has become evident that the reciprocal interactions of tumor cells with their environment are a crucial step in cancer progression. Understanding the molecular mechanisms by which melanoma manipulates its local environment to invade is instrumental to the identification of new therapeutic approaches. Our group has studied the regulation and functional role of several proteolytic enzymes (MMPs and ADAMs), which allows tumor cells to modify the peritumoral areas to produce a tumor-favorable environment. We made several efforts and contributed to understanding how an altered balance of connective tissue metabolism that disrupts skin homeostasis leads to cancer progression. The overall focus of our current research is to identify authentic substrates and signal cascades initiated by proteases (MMP13, -14 and ADAM-9, -15) and receptors that contribute in different manners to melanoma development, but also to tissue repair and skin homeostasis. To address these issues, we use state-of-the-art in vitro models to study migration, proteolysis, and invasion. Still, we also use mice models of complete protease deletion and various in vivo models for melanoma growth (grafting and spontaneous), tissue repair, and fibrosis (bleomycin-induced). To further uncover the function of MMP-14 and to identify the identity of the cellular source, we generated by conditional gene targeting strategies, several cell-specific deletion mouse models to unravel the function of MMP-14 in the cell types of the skin.
These mouse models will provide valuable insights into it‘s functional roles during disease including melanoma progression, but also into regeneration, inflammation and fibrosis.
Further studies from our group are aimed to understand how cellular communication between melanoma cells and cells of the microenvironment contribute to alter the microenvironment supporting the response to melanoma therapy and in acquired resistance.
Pach E, Brinckmann J, Rübsam M, Kümper M, Mauch C, Zigrino P: Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth. Cancers (Basel). Apr 20;13(8):1984, 2021.
Abety AN, Pach E, Giebeler N, Fromme JE, Aramadhaka LR, Mauch C, Fox JW, Zigrino P: Loss of ADAM-9 leads to modifications of the extracellular matrix modulating tumor growth. Biomolecules. Sep 7; 10(9):E1290, 2020
Ayachi O, Barlin M, Broxtermann PN, Kashkar H, Mauch C, Zigrino P: The X-linked inhibitor of apoptosis protein (XIAP) is involved in melanoma invasion by regulating cell migration and survival. Cell Oncol (Dordr). Jun; 42(3):319-329, 2019
Giebeler N, Schönefuß A, Landsberg J, Tüting T, Mauch C, Zigrino P: "Deletion of ADAM-9 in HGF/CDK4 mice impairs melanoma development and metastasis. Oncogene 36(35):5058-5067 (2017)
Mammadova-Bach E, Zigrino P, Brucker C, Bourdon C, Freund M, De Arcangelis A, Abrams S, Orend G, Gachet C and Mangin PH: Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9. JCI Insight. 1(14):e88245, 2016
Zigrino P, Brinckmann J, Niehoff A, Lu Y, Giebeler N, Eckes B, Kadler KE, Mauch C: Fibroblasts-derived MMP-14 regulates collagen homeostasis in adult skin. J Invest Dermatol, 136(8):1575-83, 2016
Taylor SH, Yeung C-J C, Kalson NS, Lu Y, Zigrino P, Starborg T, Warwood S, Holmes DF, Canty-Laird EG, Mauch C, and Kadler KE: Matrix metalloproteinase 14 is required for fibrous tissue expansion. Elife. 4, doi: 10.7554/eLife.09345, 2015
Witt A, Seeger J, Coutelle O, Zigrino P, Broxtermann P, Andree M, Brinkmann K, Juengst C, Schauss A, Wohlleber D, Knolle P, Krönke M, Mauch C, Schüll S and Kashkar H: IAP antagonization promotes inflammatory destruction of vascular endothelium. EMBO reports 16(6):719-27, 2015
Abety AN, Fox JW, Schönefuß A, Zamek J, Landsberg J, Krieg T, Blobel C, Mauch C, and Zigrino P: Protective role of host-derived ADAM-9 in the progression of malignant melanoma J Invest Dermatol 132(10):2451-8, 2012
Schmidt P, Kopecky C, Hombach A, Zigrino P, Mauch C, Abken H: Eradication of melanomas by targeted elimination of a minor subset of tumor cells. Proc Natl Acad Sci U S A. 8;108 (6):2474-9, 2011