Single-cell RNA sequencing reveals tumor heterogeneity in small cell neuroendocrine cervical carcinoma.

Small cell neuroendocrine cervical carcinoma (SCNECC) is an aggressive gynecological malignancy with poor prognosis. The precision therapeutic strategies for SCNECC are severely limited by the complex tumor microenvironment. Here, we mapped the single-cell landscape of a total of six samples from matched SCNECC cancerous foci and normal adjacent cervical tissues. Through analysis of 68,455 high-quality cells, malignant epithelial cells were identified with increased neuroendocrine differentiation and reduced keratinization. Within four epithelial cell clusters, the key transcription factors ASCL1, NEUROD1, POU2F3, and YAP1 defined molecular subtypes. Transitional trajectory among subtypes characterized two distinct carcinogenesis pathways in SCNECC. The P-type SCNECC showed potentially enhanced immune infiltration over other subtypes. Intercellular communication analysis identified several immune checkpoints and differentially expressed signaling pathways among subtypes. Through western blotting, the TC-YIK cell line was identified as an N-type SCNECC cell with high expression of SLFN11 and mTOR. Based on immunohistochemical staining of malignant subtyping markers, a cohort of 66 SCNECC patients from our hospital were divided into five subtypes. We further combined YAP1 expression with other clinicopathological factors (Cox p < 0.05) to establish a prognostic nomogram. Overall, these findings provide clues for tumorigenesis, precision treatments and prognostic prediction in SCNECC.