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Published on: August 25, 2020
Single-cell RNA sequencing reveals tumor heterogeneity in small cell neuroendocrine cervical carcinoma
Xuesong Xiang1,2, Xiang Tao3, Keqin Hua4,5
1Department of Gynecological Oncology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P. R. China.
Abstract:
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.
Insights
This study reveals distinct molecular subtypes and carcinogenesis pathways in small cell neuroendocrine cervical carcinoma (SCNECC). Findings offer insights into SCNECC tumorigenesis, guiding precision treatments and prognostic prediction.
Area of Science:
- Gynecologic Oncology
- Cancer Genomics
- Single-cell Analysis
Background:
- Small cell neuroendocrine cervical carcinoma (SCNECC) is an aggressive malignancy with limited therapeutic options.
- The complex tumor microenvironment hinders precision treatment strategies for SCNECC.
Purpose of the Study:
- To map the single-cell landscape of SCNECC and identify molecular subtypes.
- To elucidate distinct carcinogenesis pathways and intercellular communication networks.
- To develop a prognostic model for SCNECC.
Main Methods:
- Single-cell RNA sequencing of six matched SCNECC and normal cervical tissue samples.
- Bioinformatic analysis of 68,455 high-quality cells to identify epithelial cell clusters and transcription factors.
- Western blotting, immunohistochemical staining, and Cox proportional hazards model for prognostic nomogram development.
Main Results:
- Identified malignant epithelial cells with increased neuroendocrine differentiation and reduced keratinization.
- Defined four epithelial cell clusters and key transcription factors (ASCL1, NEUROD1, POU2F3, YAP1) for molecular subtyping.
- Characterized two distinct carcinogenesis pathways and identified P-type SCNECC with enhanced immune infiltration.
- Discovered immune checkpoints and signaling pathways involved in intercellular communication.
- Classified 66 SCNECC patients into five subtypes and developed a YAP1-based prognostic nomogram.
Conclusions:
- The study provides a comprehensive single-cell atlas of SCNECC, revealing molecular heterogeneity.
- Identified distinct subtypes and carcinogenesis pathways, offering potential targets for precision therapy.
- Established a prognostic nomogram for improved patient outcome prediction in SCNECC.
