Accelerated Aging and Microsatellite Instability in Recessive Dystrophic Epidermolysis Bullosa-Associated Cutaneous Squamous Cell Carcinoma
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PROVIDER: PRJNA992516 | ENA |
REPOSITORIES: ENA
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Project description:The goal of this study is to discover fibroblast subpopulations relevant to recessive dystrophic epidermolysis bullosa
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Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a severely debilitating disorder caused by mutations in COL7A1 and is characterized by extreme skin fragility, chronic inflammation and fibrosis. A majority of RDEB patients develop squamous cell carcinoma (SCC), a highly aggressive skin cancer with limited treatment options currently available. In this study, we utilized a novel approach leveraging WGS and RNA-seq across three different tissues in a single RDEB patient to gain insight into possible mechanisms of RDEB-associated SCC progression and to identify potential novel therapeutic options. As a result, we identified PLK-1 as a possible candidate for targeted therapy and discovered microsatellite instability and accelerated aging as factors potentially contributing to the aggressive nature and early onset of RDEB SCC.
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Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a monogenetic skin disorder caused by mutations in the COL7A1 gene. Missing type VII collagen leads to severe blister formation and frequent chronic wounds. Patients suffering from RDEB are prone to develop particulary aggressive squamous cell carcinoma (SCC), representing the major cause of mortality. This dataset provides Affymetrix microarray (ClariomD) based whole transcriptome data on RNA isolated from cultured primary RDEB keratinocytes (RDEB-KC) as well as RDEB squamous cell carcinoma (RDEB-SCC). Cells were derived from punch biopsies or tumor resections from patients with confirmed diagnosis recessive dystrophic epidermolysis bullosa (RDEB). Primary KC and SCC were cultivated in fully defined medium till subconfluency. Total RNA was isolated and microarray assay performed.
2020-04-22 | GSE130925 | GEO
Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a monogenetic skin disorder caused by mutations in the COL7A1 gene. Missing type VII collagen leads to severe blister formation and frequent chronic wounds. Patients suffering from RDEB are prone to develop particulary aggressive squamous cell carcinoma (SCC), representing the major cause of mortality. This dataset provides Affymetrix microarray (miRNA4.1) based whole transcriptome data on RNA isolated from cultured primary keratinocytes (KC) as well as squamous cell carcinoma (SCC). Cells were derived from punch biopsies or tumor resections from either healthy donors or SCC patients with or without the diagnosis recessive dystrophic epidermolysis bullosa (RDEB). Primary KC and SCC were cultivated in fully defined medium till subconfluency. Total RNA was isolated and microarray assay performed.
2020-04-22 | GSE130767 | GEO
Project description:Recessive dystrophic epidermolysis bullosa (RDEB), intractable skin genetic disease, is caused by mutations in COL7A1. Most RDEB patients have mutations in a compound heterozygous manner. We established an RDEB model mouse with patient type mutations in a compound heterozygous manner. We selected two mutations, c.5818delC and E2857X, which is recurrently identified in human RDEB cohort, and introduced the mutations at corresponding locations of the mouse genome. We analyzed the established mouse by single cell RNA-seq to clarify how loss of functional type VII collagen impact on the integrity of skin.
2022-03-16 | GSE181357 | GEO
Project description:Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
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Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Pre-clinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support clinical development of antivirals for treatment of patients with RDEB and potentially other fibrotic diseases.
2024-03-01 | GSE254347 | GEO
Project description:Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa(DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. We developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7).
2024-06-30 | GSE229920 | GEO
Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterized by fragile skin forming blisters that heal invariably with scars. It is due to mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis. Identical COL7A1 mutations often result in inter- and intra-familial disease variability, suggesting that additional modifiers contribute to RDEB course. Here, we studied a monozygotic twin pair with RDEB presenting markedly different phenotypic manifestations, while expressing similar amounts of collagen VII. Genome-wide expression analysis in twins' fibroblasts showed differential expression of genes associated with TGF-β pathway inhibition. In particular, decorin, a skin matrix component with anti-fibrotic properties, was found to be more expressed in the less affected twin. Accordingly, fibroblasts from the more affected sibling manifested a profibrotic and contractile phenotype characterized by enhanced α-smooth muscle actin and plasminogen activator inhibitor 1 expression, collagen I release and collagen lattice contraction. These cells also produced increased amounts of proinflammatory cytokines interleukin 6 and monocyte chemoattractant protein-1. Both TGF-β canonical (Smads) and non-canonical (MAPKs) pathways were basally more activated in the fibroblasts of the more affected twin. The profibrotic behaviour of these fibroblasts was suppressed by decorin delivery to cells. Our data show that the amount of type VII collagen is not the only determinant of RDEB clinical severity, and indicate an involvement of TGF-β pathways in modulating disease variability. Moreover, our findings identify decorin as a possible anti-fibrotic/inflammatory agent for RDEB therapeutic intervention. Primary fibroblast cultures from biopsies from two twins affected by recessive dystrophic epidermolysis bullosa were analyzed. Each hybridization was performed in biological triplicate and in technical duplicate.
2014-04-03 | E-GEOD-51056 | biostudies-arrayexpress
Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a mucocutaneous blistering disease due to type VII collagen gene mutations. Transforming growth factor-β (TGF-β)-dependent fibrosis is responsible for severe RDEB complications. Reduced histone acetylation is a hallmark of fibrosis in pathologies affecting organs other than skin, where inhibition of histone deacetylses (HDACs) proved effective in reverting fibrosis. Here, HDAC inhibitor (HDACi) ability to counteract RDEB progression was investigated. We found that histone acetylation is decreased in RDEB skin and fibroblasts. Treatment with two HDACis, valproic acid (VPA) and Givinostat, counteracts RDEB fibroblast fibrotic traits, including contractility, α-smooth muscle actin expression, TGF-β1 release, and proliferation. Moreover, systemic VPA administration mitigates severe manifestations (corneal opacification and digit loss) in a RDEB mouse model. This effect associates with inhibition of skin fibrosis (presence of subcutaneous fat, thinner collagen bundles, decreased expression of fibrotic markers). Proteomic analysis of mouse skin revealed that VPA treatment decreases expression of genes involved in protein synthesis and increases levels of proteins with role in immune response. These findings highlight epigenetic changes as contributing to RDEB pathogenesis and disclose molecular mechanisms leading to skin fibrosis. Treatment with HDACi may represent a disease modifier therapeutic approach for RDEB and other skin fibrotic disorders.
2024-09-02 | GSE239569 | GEO