Exploring the pathophysiological stress response spectrum for iRhom-ADAM17-dependent signalling in skin and oesophageal tissues

• Applicants: Dr. Aaron Babendreyer; Dr. Stefan Düsterhöft
• Subject Area: Dermatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556125570

The skin and oesophagus are among the first line of defence against environmental stressors. Therefore, maintaining the homeostasis of these vital barriers is of paramount importance. Disruptions of this barrier can pave the way for various pathologies such as hyperkeratosis, unresolved infections, (chronic) inflammation and cancer. Elucidating the molecular mechanisms that govern these processes is therefore essential for the advancement of biomedical knowledge. Our project focuses specifically on the transmembrane iRhom-ADAM17 complex - a linchpin between intra- and extracellular signalling and a key player in cell surface remodelling. As a transmembrane protease/sheddase of membrane-bound proforms of mediators such as TNF or amphiregulin, ADAM17 orchestrates critical functions in inflammation, cell growth and migration in various tissues, including skin and oesophagus. The pseudoprotease iRhom in this complex is a key regulator of ADAM17 localisation, stability and activity. A mutation in iRhom2 is associated with Tylosis Oesophageal Carcinoma (TOC). This condition manifests as hyperkeratosis and increased susceptibility to oesophageal squamous cell carcinoma (OSCC), presumably due to increased ADAM17 activity. However, the role of the iRhom-ADAM17 complex in skin and oesophagus is still poorly understood. Our previous results show that the iRhom-ADAM17 complex is sensitive to inflammatory and mechanical stressors. In particular, mechanical forces are an important stressor for skin and oesophagus, but have not been well studied in the context of the iRhom-ADAM17 complex. Our project also considers the complexity of environmental stressors to which the skin and oesophagus are constantly exposed. These include mechanical forces as well as temperature changes, pH shifts, UV radiation and infections. If these factors, or a combination of them, lead to faulty signal transmission in the cells, this can result in the development of disease. Therefore, in three subprojects we will investigate the underlying signalling pathways, molecular mechanisms and systemic consequences of the iRhom-ADAM17 complex in the context of this stressor spectrum. By using state-of-the-art methods such as multiomics and AI-based bioinformatics, as well as 3D cell cultures and skin equivalent models, the project promises to provide comprehensive new insights thanks to the use of primary cells, including those derived from TOC patients. These insights will not only contribute to the understanding of the iRhom-ADAM17 complex in skin and oesophagus, but may also open up innovative therapeutic approaches for iRhom-ADAM17-dependent pathologies such as chronic inflammation and cancer.

• DFG Programme: Research Grants