Transcriptomic landscape of coexisting ovarian clear cell carcinoma and endometriosis: Insights into malignant transformation

● Spatial transcriptomics integrated with scRNA-seq elucidated EMS–OCCC transcriptomic links. ● Severe uterine EMS showed greater similarity to OCCC than to HGSOC. ● OCCC-specific genes divided into EMS epithelial and other cell-related groups. ● Distinct invasion/metastasis and metabolic pathways identified. ● Findings suggest novel molecular targets for OCCC therapy. This study investigateted the malignant transformation of endometriosis (EMS) into ovarian clear cell carcinoma (OCCC) using spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) integration. Tissues with coexisting EMS and OCCC regions were analyzed to elucidate their molecular connections. Spatial transcriptomic profiling revealed shared molecular features between OCCC and EMS, including overexpression of genes related to tissue development and apoptosis. Integration with scRNA-seq data revealed that severe uterine EMS exhibited greater transcriptomic similarities to OCCC than to non-EAOC ovarian cancer subtypes, such as high-grade serous ovarian cancer (HGSOC). Further analysis classified the OCCC-specific genes into EMS epithelial cell-specific and tumor microenvironment (TME)-related categories, highlighting their roles in pathways associated with tumor progression, invasion, and metabolic reprogramming. These findings support the transcriptomic progression pathway from EMS to OCCC, and advance our understanding of the etiology of OCCC, suggesting strategies for targeted therapy and improved diagnostics. Transcriptomic landscape of malignant transformation from EMS to OCCC. EMS cells reach the ovarian epithelium from the uterus through the fallopian tubes. In the ovarian epithelium, EMS occurs and malignantly transforms into atypical EMS. In atypical EMS, EMS-cell–specific genes such as CLDN3, RNASET2 , and GPX3 are upregulated and introduce malignant developmental biological processes, including metaplasia and epithelial cell morphogenesis. These transcriptomic alterations affect other ovarian cells and upregulate TME-related genes such as ENO1, CDH1 , and PPP1R3B , thereby promoting further malignant developmental processes, including cell population proliferation and activation of glucose metabolism, that ultimately result in OCCC morphogenesis.