O11 Spatial transcriptomic insights into the early pathogenesis of steatocystoma multiplex

Abstract Introduction and aims Steatocystoma multiplex (SM) is a genodermatosis frequently due to pathogenic KRT17 variants, where dermal cysts called steatocystomas develop all over the body. They can become inflamed and painful, causing significant psychosocial distress and reduced mobility. There is no cure. The molecular pathways leading to steatocystoma development are unknown. Initial sectioning revealed epidermal abnormalities overlying steatocysts. Our aim was to investigate the early pathogenesis of SM via spatial transcriptomic analysis of cysts at different stages of evolution. Methods We carried out spatial transcriptomic analysis using Visium HD, at 2 × 2 µm resolution, of formalin-fixed paraffin-embedded biopsy specimens of three early cysts and an established cyst, dissected into cyst wall and overlying epidermis, from three patients with SM alongside a normal skin control. We compared early cyst, established cysts and normal skin. The patients were men aged 50–83 years old. Results Differentially expressed genes related to barrier formation (SPRR4, MUCL1), inflammatory response [S100A9, S100A8 – involved in interleukin (IL)-17 signalling] and tissue remodelling (KLK6, TMPRSS11E) were significantly upregulated in steatocystoma cyst walls of all SM samples, as were the wound-healing keratin KRT17 and its binding partners KRT16, KRT6A and KRT6B. Analysis of the epithelial stalk joining cyst and epidermis revealed elevated NOTCH1 and SOSTDC1, Wnt/β-catenin regulators. One early cyst was surrounded by significant lymphocytic infiltration with upregulation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) genes in that region, particularly JAK3. Conclusions This is the first study to use spatial transcriptomics to investigate SM pathogenesis. The upregulated genes are consistent between different patient cyst samples and some were also reported in a spatial transcriptomic analysis of early hidradenitis suppurativa nodules, a clinically similar condition. We identify new potential therapeutic targets, the IL-17 and JAK/STAT pathways. This study is limited by small sample size. Future work will validate these findings using multiplex imaging of archival samples.