Tylosis with oesophageal cancer (TOC) is a rare syndrome associated with focal non-epidermolytic palmoplantar keratoderma (NEPPK), a high, lifetime risk of developing oesophageal squamous cell carcinoma (OSCC), and gain-of-function mutations in RHBDF2 (encoding iRhom2). To date, there is a lack of a useful and representative model to study the development of NEPPK and OSCC in vivo, which might aid our understanding of hyperproliferative skin disease and cancer predisposition. CRISPR-Cas9 was used to generate a novel mouse model of TOC that contains a heterozygous Rhbdf2I156T/+ mutation which mirrors the UK TOC family mutation, RHBDF2I186T/+. Mice were comprehensively phenotyped and bulk and spatial RNA-sequencing was performed on forepaw skin. First observations found that TOC mice developed thickened, reddened footpads around ~8 months of age, and TOC paw epidermis was significantly thicker than wildtype comparisons. This matched the human condition, in which NEPPK presents late and is restricted to weight-bearing areas. Bulk RNA-Sequencing identified an upregulation of keratin genes, Krt14, Krt16, and Krt17; alarmins, S100a8 and S100a9; and the AP-1 transcription factor subunit, Fos. Pathway analysis revealed that TNF-α signalling was enriched in TOC forepaw skin, which matched human TOC skin, and is directly linked to iRhom2, which regulates the TNF-α sheddase, ADAM17. Spatial RNA-Sequencing was performed to reveal the exact location of these transcriptomic events, and gene expression was found to vary considerably between footpad and sole regions. Moreover, Fos was upregulated in TOC sole, which mirrored the bulk data, and highlights a possible role for AP-1 in NEPPK development. We introduce a new, clinically representative mouse model of the NEPPK and OSCC syndrome, TOC. Mice present with focal paw lesions, and transcriptomic analyses have revealed several genes which might be key drivers of focal NEPPK. Further, this model may enhance our understanding of hyperproliferative skin biology.

ESDR173 - A Model to Unravel Pathways Underpinning Palmoplantar Homeostasis and Disease

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.