Topical sirolimus is increasingly being used in the treatment of several skin disorders. We previously demonstrated in a double-blind study that applying topical sirolimus for 12 weeks effectively reduced the risk of keratinocyte cancer in solid organ transplant recipients. Additionally, we observed a reduction in actinic keratoses at 12 weeks and a decrease in the occurrence of intraepidermal carcinomas 24 months post-treatment.
To gain deeper insights into patients' skin samples after 12 weeks of treatment (n=10 treated vs. n=10 placebo), we employed Visium Spatial Transcriptomics.
We identified the effects of sirolimus on keratinocytes: downregulation of cell proliferation and mitosis, impairment of the differentiation process through increased expression of keratin 14 and integrins, and downregulation of NOTCH signaling. Additionally, under mTOR inhibition, some mitochondrial complexes involved in the electron transport chain were significantly downregulated, suggesting a potential pivotal role of mitochondria in carcinogenesis. Our study revealed metabolic rewiring not only in keratinocytes at a late stage of differentiation but also at early stages and in the basal layer, indicating that the effect begins earlier in the differentiation process.
In conclusion, our findings highlight that the chemopreventive effect of mTor inhibition is primarily mediated through an imbalance of differentiation and proliferation, which can be triggered by metabolic rewiring.