Single-cell RNA sequencing provides insights into the potential cellular origins and microenvironment of Extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential. The exact origin of the tumor is still undefined. To explore potential cellular origin-related signals and depict a relatively comprehensive cellular landscape of EMPD, we collected 50,180 cells from patients with EMPD. We detected a distinct basal keratinocyte cell population characterized by New York Breast-1 (NY-BR-1) expression, which exhibited a transcriptional trajectory toward Paget-like phenotype. We also presented a comprehensive single-cell profile of immune cells and fibroblasts in EMPD. The fibroblasts exhibited a markedly central position in outgoing and incoming signaling interactions. The upregulation of the MK pathway and the downregulation of the MIF pathway in EMPD may promote fibroblast-immune crosstalk and tumor progression. This study provided a novel perspective on potential origin-related transcriptional programs in EMPD and highlighted a global reprogramming of cell-cell communication in EMPD, driven predominantly by fibroblast-derived interactions.