The Role of Senescence in the Step-by-Step Development of Endometrial Cancer

Endometrial cancer (EC) is one of the most prevalent gynecological malignancies worldwide. Atypical endometrial hyperplasia (AEH) is a premalignant condition with a substantial risk of progression to EC, with the endometrioid subtype (EEC) being the most common. In this study, we investigated the escape-from-senescence concept as a model for the malignant progression from AEH to EEC by bioinformatic analysis of single-cell RNA sequencing data. Unciliated epithelial cells from AEH and EEC tissues exhibited significantly higher levels of senescence compared with those from normal endometrium. Both the proportion of senescent cells (SCs) and their senescence scores remained comparable between hyperplasia and cancer. Despite pronounced genomic instability, SCs in EEC showed no evidence of cell cycle re-entry. RNA velocity analysis revealed no transcriptional trajectories indicating a transition from senescent to non-senescent states in the EEC group. While SCs in AEH and EEC shared similar senescence-associated transcriptional profiles, they demonstrated differences in immunomodulatory activities with enhanced immunosuppressive signaling in the EEC group compared to AEH. Thus, we found no evidence supporting the occurrence of large-scale senescence escape and subsequent malignant conversion of epithelial SCs during EC development. Instead, senescence appears to represent a generalized stress response that persists throughout both premalignant and malignant stages.