The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget’s disease

Abstract

Mammary and extramammary Paget’s Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways — including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Integrative bioinformatics approaches to map key biological markers and therapeutic drugs in Extramammary Paget’s disease of the scrotum

“…Gene Expression Omnibus (GEO) database in National Center for Biotechnology Information (NCBI) is a freely available public database, enclosing the gene profiles [19]. Expression profile of GSE117285 based on GPL17077 platform (Agilent-039494 SurePrint G3 Human GE v2 8x60K array) was retrieved from NCBI-GEO database [20]. Dataset include 4 controls and 4 EMPD cases.…”

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea

“…We conducted a clinical trial in 18 adult female patients with moderate-to-severe rosacea (ETR and PPR) for 4-week topical rapamycin or placebo ointment treatment. Rosacea skin lesions were topically applied with 0.4% FDA-approved rapamycin or placebo ointment twice a day for 4 weeks as previously described (Song et al, 2020). All participants underwent the following evaluation at baseline and follow-up visit (at 4 weeks).…”

Extramammary Paget Disease of Peristomal Skin Secondary to Bladder Urothelial Carcinoma

“…Currently, the exact mechanism underlying EMPD is unknown, but two widely known theories exist, namely the epidermotropic and transformation theories. The epidermotropic theory is more commonly accepted and suggests migration of adenocarcinoma cells into the epidermis, while the transformation theory postulates in situ malignant transformation of basal keratinocytes [3]. However, there remains a lack of evidence for either therefore it is recommended that all patients with pruritic eczematous lesions of apocrine gland-bearing skin who fail to respond to standard topical treatment after 4-6 weeks receive skin biopsy of the affected area for diagnosis [1,2].…”

“…There have been several studies which seek to identify biomarkers and signaling pathways in an effort to guide development of treatments. Specifically, the Msi1-mTOR pathway has been cited to promote Paget cell conversion of keratinocytes, suggesting the utility of Rapamycin as a novel therapy in patients expressing this phenotype [3]. Similarly, HER2 and downstream molecules in the RAS-RAF-MEK and PI3K-AKT-mTOR pathways have been identified as potential targets for treatment [4].…”