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.

乳房和乳房外佩吉特病 (PD) 是一种恶性皮肤癌，其特征是出现佩吉特细胞。尽管很容易诊断，但其发病机制仍不清楚。在这里，单细胞 RNA 测序鉴定了不同的细胞状态、新型生物标志物和信号通路——包括与乳房外 PD 相关的 mTOR。有趣的是，我们在人PD皮肤基底上皮细胞中发现了MSI1异位过度表达，并表明Msi1在小鼠表皮基底层中的过度表达在组织病理学、单细胞和分子水平上模仿了人类PD。使用这种小鼠模型，我们鉴定了可转化为人类佩吉特细胞的佩吉特样细胞的新生物标志物。此外，单细胞轨迹、RNA速度和谱系追踪分析揭示了假定的角质形成细胞向佩吉特样细胞的转化，支持了疾病发病机制的原位转化理论。从机制上讲，Msi1-mTOR 途径驱动角质形成细胞-Paget 样细胞转化，用雷帕霉素抑制 mTOR 信号传导可显着挽救 Msi1 过表达转基因小鼠的 Paget 样表型。局部雷帕霉素治疗可改善人类乳房外 PD 相关症状，表明 mTOR 抑制可作为 PD 的一种新型治疗方法。