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

TitleFibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.
Publication TypeJournal Article
Year of Publication2019
AuthorsChacón-Solano, E, León, C, Díaz, F, García-García, F, García, M, Escámez, MJ, Guerrero-Aspizua, S, Conti, CJ, Mencía, Á, Martínez-Santamaría, L, Llames, S, Pévida, M, Carbonell-Caballero, J, Puig-Butillé, JA, Maseda, R, Puig, S, de Lucas, R, Baselga, E, Larcher, F, Dopazo, J, Del Rio, M
JournalBr J Dermatol
Volume181
Issue3
Pagination512-522
Date Published2019 09
ISSN1365-2133
KeywordsAdolescent; Adult; Biopsy; Blister; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibroblasts; Fibrosis; Gene Expression Regulation; Healthy Volunteers; Humans; Infant; Infant, Newborn; Male; Middle Aged; mutation; Periodontal Diseases; Photosensitivity Disorders; Primary Cell Culture; RNA-seq; Skin; Xeroderma Pigmentosum; Young Adult
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-β 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.

DOI10.1111/bjd.17698
Alternate JournalBr J Dermatol
PubMed ID30693469
PubMed Central IDPMC6850467
Grant ListAvanCell-CM S2017/BMD-3692 / / Comunidad de Madrid / International
AGAUR 2014_SGR_603 / / Catalan Government / International
SAF2013-43475R / / Ministerio de Economía y Competitividad / International
SAF2017-86810-R / / Ministerio de Economía y Competitividad / International
SAF2017-88908-R / / Ministerio de Economía y Competitividad / International
H2020-INFRADEV-1-2015-1 / ELIXIR-EXCELERATE-ref.67 / / European Union / International
HEALTH-F2-2011-261392 / / European Union / International
PI14/00931 / / Instituto de Salud Carlos III / International
PI15/00716 / / Instituto de Salud Carlos III / International
PI15/00956 / / Instituto de Salud Carlos III / International
PI17/01747 / / Instituto de Salud Carlos III / International
PT13/0001/0007 / / Instituto de Salud Carlos III / International
PT17/0009/0006 / / Instituto de Salud Carlos III / International