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
Date Published2019 Jan 28
ISSN1365-2133
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.

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