Fibroblasts activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer‐prone genodermatoses

Summary

Background

Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and Xeroderma pigmentosum 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 that 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

Inter‐disease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and 4 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 analysis validated the RNA‐Seq data. In addition, enzyme‐linked immunosorbent assay (ELISA) revealed increased circulating levels of periostin in RDEB patients.

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 the abnormal ECM deposition and under‐expression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS.

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