Single cell sequencing provides new insights on cervical cancer and its future therapies
As January is Cervical Cancer Awareness Month, we bring you here a selection of recent studies that examined cervical cancer at single cell resolution.
Cervical cancer is a female malignancy, ranking the fourth of incidence and the fourth of mortality across all cancer types in women (1). Almost all cases of the disease are caused by human papillomavirus (HPV) infection. If detected early, cervical cancer is one of the most successfully treatable forms of cancer. Development of cellular and molecular diagnostic methods in the last decades, such as Pap smear and HPV tests, as well as vaccines against HPV can prevent the vast majority of cervical cancers.
Therapeutics against advanced cervical cancer are available, but due to the inter-tumor and intra-tumor heterogeneity, the response rates are low (2,3). Therefore, understanding the heterogeneity of cervical cancer and the components of the tumor microenvironment is key for the development of personalized therapeutic approaches. In addition, single cell transcriptomics data may enable us to get deeper insights in the cervical carcinogenesis, leading to the identification of new potential therapeutic targets.
Read our selection of single cell sequencing articles with findings that may shape the future of therapies for cervical cancer.
Cellular heterogeneity and molecular stratification of cervical cancer
Li and colleagues (4) have performed single cell RNA sequencing on three cervical cancer tumors with paired normal adjacent non-tumor samples revealing that epithelial cells from tumor samples showed distinct transcriptional features compared to those from normal samples. The epithelial signature genes derived from scRNA-seq were further used to deconvolute bulk RNA-seq data of cervical cancer, identifying four different cervical cancer subtypes, namely hypoxia (S-H subtype), proliferation (S-P subtype), differentiation (S-D subtype), and immunoactive (S-I subtype) subtype (4). The S-H subtype showed the worst prognosis, while cervical cancer patients of the S-I subtype had the longest overall survival time, suggesting that these results may lay the foundation for precision prognostic and therapeutic stratification of cervical cancer (4).
Figure 1. Tumor heterogeneity of cervical cancer at single cell resolution. UMAP dimensionality reduction of all cells (left), heatmap with the relative expression of top marker genes in each cell type (middle) and the cell numbers in cervical cancer tumor and normal adjacent non-tumor samples for each cell type (right). (Image from (4), http://creativecommons.org/licenses/by/4.0/).
Enhanced antitumor immunity of macrophages in the tumor microenvironment
Yang and colleagues (5) have focused on the characterization of the tumor-associated macrophages (TAMs) of stage I and II cervical cancer patients with single cell RNA-seq. The single cell analysis revealed that macrophage phenotypes derived from the stage I patients showed significant activation of the IFN-α response pathway (5). These results pinpointed comparative immunological footprints of macrophages between the treatments containing caerin 1.1/1.9 in murine models and human cervical cancer stage I patients, strongly suggesting that caerin 1.1/1.9 are promising agents to be included in cancer immunotherapy that could alter the tumor microenvironment to be more immune active (5).
Figure 2. Comparative analysis of the functions of macrophages in the tumor microenvironment (TME) of early (CCI) and late (CCII) stage cervical cancer patients. t-SNE distribution of macrophage subtypes identified, including resident-like, TAM, M2-like, MΦ/DC, and M1-like MΦs (left). Proportions of each MΦ subpopulation in the MΦs of the patients (top right) and the proportion of individual patient MΦ in each subpopulation (bottom right). (Image from (5), http://creativecommons.org/licenses/by/4.0/).
Transcription factors associated with cervical cancer
Jiang and Chen (6) have investigated transcription factors involved in cervical carcinogenesis in order to identify new therapeutic targets. Using public single-cell RNA-sequencing, bulk RNA-seq, and microarray datasets, five homeobox-containing transcription factors (EMX2, HOXC6, ISL1, HOPX, and MSX1) were identified as dysregulated in cervical cancer, indicating their particular involvement in cervical cancer tumorigenesis (6). The high expression of EMX2 transcription factor in normal female reproductive tract tissues has been shown to be lost in cervical cancer and the overexpression of EMX2 in HeLa cells has led to decreased cell viability, suggesting that EMX2 acts as a tumor suppressor in cervical cancer and therefore may be exploited as a potential therapeutic target candidate (6).
Figure 3. Transcriptional regulatory network for EMX2 and target genes identifies PDZRN3 as a potential target. PDZRN3 is also target of human papillomavirus (7). (Image from (6), http://creativecommons.org/licenses/by/4.0/).
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