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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 lineagetracing 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.