Unravelling the Epidermolysis Bullosa-Extracellular Matrix- Cutaneous Squamous Cell Carcinoma Development Triad

Dystrophic epidermolysis bullosa (DEB) is a genetic skin disease caused by COL7A1 gene mutations that encodes collagen VII extracellular matrix (ECM) protein, the major component of the anchoring fibrils in the dermal-epidermal junction of human skin. The impaired function of collagen VII leads to decreased resistance of the skin against friction and, consequently, results in clinically visible blistering and development of chronic wounds that lead to tissue fibrosis and scaring. The disease spectrum ranges from localized blisters to severe generalized phenotypes with multi-organ involvement depending if the inheritance pattern is dominant (DDEB) or recessive (RDEB).

The most serious complication in RDEB patients is the development of cutaneous squamous cell carcinoma (cSCC) that occurs in nearly all patients, being ultimately the main cause of death due to tumor metastization. In contrast, non-RDEB patients have a low risk of developing cSCC and metastases are very rare. However, despite the huge differences in the clinical manifestation and prognosis, there is no evidence that RDEB and non-RDEB cSCC are biological distinct entities. The mechanisms underlying the unusual rapid progression and aggressiveness of cSCC in RDEB patients are unknown, although it has been suggested that the microenvironment plays a key role. It seems that, even in the absence of the tumor, the ECM of RDEB reassembles aspects of cSCC stroma such as less abundant basal membrane proteins, enhanced levels of matrix metalloproteinases and increased TGF-β signaling. Taking together these findings, we hypothesized that the ECM composition and its mechanical properties contribute to a permissive microenvironment for cSCC progression in RDEB patients.

In this sense, our project aims to explore the molecular mechanisms underlying cSCC development in patients with RDEB, in particular, the contribution of ECM composition and stiffness for tumor establishment and progression. For that, we propose an innovative approach based on cell sheet engineering to create representative skin microenvironments of DEB variants that will allow us to understand how differences in the ECM composition/stiffness influence the interaction between malignant keratinocytes and its microenvironment. This represents a pioneer approach to better understand ECM role on cSCC progression and to generate further knowledge on DEB and associated complications.

Acknowledgements: The authors would like to acknowledge FCT for grant SFRH/BD/137766/2018 (MDM), the ERC Consolidator Grant – ECM_INK (ERC-2016-COG-726061), NORTE-01-0145-FEDER-000021 (MTC), the European Union for The Discoveries Centre for Regenerative and Precision Medicine (H2020-WIDESPREAD-2014-1-739572) and the Gene2Skin Project (H2020-TWINN-2015-692221).