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Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.

ABSTRACT: BACKGROUND:Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. OBJECTIVES:To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. METHODS:We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. RESULTS:Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. CONCLUSIONS:Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-? signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

SUBMITTER: Chacon-Solano E

PROVIDER: S-EPMC6850467 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.

Chacón-Solano E E León C C Díaz F F García-García F F García M M Escámez M J MJ Guerrero-Aspizua S S Conti C J CJ Mencía Á Á Martínez-Santamaría L L Llames S S Pévida M M Carbonell-Caballero J J Puig-Butillé J A JA Maseda R R Puig S S de Lucas R R Baselga E E Larcher F F Dopazo J J Del Río M M

The British journal of dermatology 20190415 3

<h4>Background</h4>Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.<h4>Objectives</h4>To investigate, by means of comparative gene expression analysis, the rol ...[more]

PMID: 30693469

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Project 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.

Project description:AimsHeart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix.Methods and resultsEight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817.ConclusionsMMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.

Dataset Information

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.

Publications

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.

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