Journal Article

Integrated single-cell transcriptome analysis of the tumor ecosystems underlying cervical cancer metastasis

Yang, Shimin, Hua, Keqin, Li, Chunbo, Liu, Danyang

2022

Overview

Cervical cancer (CC) is one of the most frequent female malignancies worldwide. However, the molecular mechanism of lymph node metastasis in CC remains unclear. In this study, we investigated the transcriptome profile of 51,507 single cells from primary tumors, positive lymph nodes (P-LN), and negative lymph nodes (N-LN) using single-cell sequencing. Validation experiments were performed using bulk transcriptomic datasets and immunohistochemical assays. Our results indicated that epithelial cells in metastatic LN were associated with cell- cycle-related signaling pathways, such as E2F targets, and mitotic spindle, and immune response-related signaling pathways, such as allograft rejection, IL2_STAT5_signaling, and inflammatory response. However, epithelial cells in primary tumors exhibited high enrichment of epithelial-mesenchymal translation (EMT), oxidative phosphorylation, and interferon alpha response. Our analysis then indicated that metastasis LN exhibited an early activated tumor microenvironment (TME) characterized by the decrease of naive T cells and an increase of cytotoxicity CD8 T cells, NK cells, FOXP3+ Treg cells compared with normal LN. By comparing the differently expressed gene of macrophages between tumor and metastatic LN, we discovered that C1QA+ MRC1 low macrophages were enriched in a tumor, whereas C1QA+ MRC1 high macrophages were enriched in metastatic LN. Finally, we demonstrated that cancer-associated fibroblasts (CAFs) in P-LN were associated with immune regulation, while CAFs in tumor underwent EMT. Our findings offered novel insights into the mechanisms of research, diagnosis, and therapy of CC metastasis.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Biomarkers / CD8 antigen / CD8-Positive T-Lymphocytes / Cell cycle / Cervical cancer / Clustering / Cytotoxicity / E2F protein / Ecosystem / Epithelial cells / Female / Foxp3 protein / Gene expression / Genomics / Graft rejection / Humans / Immune system / Immunology / Immunoregulation / Inflammation / Lymph nodes / Lymphatic system / Lymphocytes T / Macrophages / Malignancy / Medical prognosis / Metastases / Metastasis / metastatic lymph node / Molecular modelling / Oxidative phosphorylation / Patients / Signal transduction / Single-Cell Gene Expression Analysis / single-cell sequencing / Software / Stat5 protein / Statistical analysis / T-Lymphocytes, Regulatory / Transcriptomes / Transcriptomics / tumor heterogeneity / Tumor microenvironment / Tumor Microenvironment - genetics / Tumors / Uterine Cervical Neoplasms