Spatially Resolved Epithelial–Immune Heterogeneity Identifies an Endometriosis Subtype with Molecular Features of Endometriosis-Associated Ovarian Cancer

Iacobelli V, Valentina Iacobelli, Mastrantoni L, Luca Mastrantoni, Alivernini S, Stefano Alivernini, Giulia Scaglione, Scaglione G, Antonio Agostini, Agostini A, Giulia Mantini, Mantini G, Piermattei A, Alessia Piermattei, Federica Persiani, Persiani F, Floriana Camarda, Camarda F, Trozzi R, Rita Trozzi, Francesca Sillano, Sillano F, D’Agostino MA, Maria Antonietta D’Agostino, Schett G, Georg Schett, Carbone C, Carmine Carbone, Scambia G, Giovanni Scambia, Anna Fagotti, Fagotti A, Camilla Nero, Nero C
In: Research Square · 2026 · doi:10.21203/rs.3.rs-10497180/v1 · W7204129191
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Abstract

Abstract Evidence suggests that clear cell and endometrioid ovarian carcinoma may arise from endometriosis. We previously identified that some endometriosis lesions exhibit a “cancer-like” PD-1/PD-L1 positive staining similar to endometriosis-associated ovarian cancers. If this condition is associated with oncogenic signaling and immune tolerance is currently unknown. Using spatial transcriptomics, we mapped epithelial cells, T lymphocytes and macrophages in 14 patients including simple endometriosis (n = 2), atypical endometriosis (n = 2), PD-L1-positive “cancer-like” endometriosis (n = 4), endometriosis-associated clear cell (n = 3) and endometrioid ovarian carcinoma (n = 3). We found that epithelial cells in cancer-like endometriosis, despite a conventional histological appearance, display significant enrichment in oncogenic signaling, extracellular matrix remodeling and wound-healing programs. This phenotype is further defined by epithelial NNMT and MUC5B expression, subepithelial neutrophil infiltration, and a shift toward an M2-macrophage-dominant, T-CD8 + cell depleted microenvironment. Proliferative signaling was enriched in endometroid carcinoma and adjacent endometriotic epithelium, while secretory signaling in cancer-like endometriosis, clear cell carcinoma and adjacent endometriotic areas. Our findings support a model of endometriosis-associated tumorigenesis through two different mechanisms: a damage-repair/inflammatory loop mimicking a “window-of-implantation-like” secretory niche or a hormone-driven proliferative signaling, providing a spatial framework for risk stratification.

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