Understanding the early evolution of steatocystoma cyst formation

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Steatocystoma multiplex (SM) is a debilitating disease characterised by the development of multiple cysts in the skin of the proximal limbs and trunk. This can cause significant psychosocial distress, particularly given the time of onset, classically at adolescence. Furthermore, these cysts frequently get inflamed, becoming red and painful and affecting mobility and sexual function, causing embarrassment. There is no cure. Current treatments, including serial excision or drainage, are time consuming and not preventative.In SM, a change to the keratin-17 gene (KRT17) which encodes the K17 protein involved in the formation of sebaceous glands (structures near hairs which have special oil-secreting cells) stops it functioning normally, although we do not understand why this causes cysts to form. The cyst wall structure and protein expression pattern of the cysts which form resembles the sebaceous duct from which sebum (oil on surface of the skin) is excreted from the sebaceous gland. The cysts are located in the dermis (the middle layer of the skin) but pathology studies from decades ago identified a fibrous band connection from the cyst to the epidermis (the top layer of skin). We do not know why or how this forms.Our aim is to understand what genes and signalling pathways cause these cysts to form to enable us to target them with therapies to prevent cyst formation.We have preliminary data that the epidermis (upper layer of the skin) overlying small, early cysts is highly abnormal (with lots of small dividing skin cells) and may contain sebocytes (specialist cells of the sebaceous gland described above). We will investigate this by analysing what genes are expressed by the skin overlying and surrounding the cyst in early cysts (via spatial transcriptomics). We will then validate possible signalling pathways identified by these genes by staining sections of these cysts for the proteins the genes express. We will also investigate the lipid composition of the cyst contents and sebum on the skin of patients compared to unaffected control participants in collaboration with our lipid expert partners in Italy. Modern lipid analysis has never before been attempted in SM. We think the sebum of SM patients may be pro-inflammatory and this could be what causes individual steatocystomas to become inflamed. Understanding this will give us insights into how to treat and stop the inflammation happening. We will then use cells carrying the altered KRT17 gene and normal control cells to test treatments targeting the signalling pathways we have found from the identified genes and proteins. Possible effective treatments could then be taken into drug development pathways or a drug repurposing pathway to ultimately offer a treatment to patients suffering from this debilitating disease.Apart from SM, altered KRT17 expression is also found in other conditions, including hidradenitis suppurativa (causing boils in the groin and underarm areas) which is clinically similar to inflamed SM, psoriasis and many cancers, where it is a well recognised poor prognostic indicator. Insights into KRT17-related pathways may also inform understanding of the pathophysiology and treatment of these conditions. Increasing understanding of the KRT17 gene may also help elucidate the function and roles of the many keratin proteins, which are highly expressed throughout the skin and associated structures such as the hair follicle and sweat glands and can cause disease when there is a genetic error (mutation).