Unraveling the landscape of non-melanoma skin cancer through single-cell RNA sequencing technology

Abstract

Non-melanoma skin cancer (NMSC) mainly includes basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma, showing a low mortality rate but the highest incidence worldwide. In recent decades, research has focused on understanding the pathogenesis and clinical treatments of NMSC, leading to significant advances in our knowledge of these diseases and the development of novel therapies, including immunotherapy. Nevertheless, the low to moderate objective response rate, high recurrence, and therapeutic resistance remain persistent challenges, which are partly attributable to the intratumoral heterogeneity. This heterogeneity indicates that tumor cells, immune cells, and stromal cells in the tumor microenvironment can be reshaped to a series of phenotypic and transcriptional cell states that vary in invasiveness and treatment responsiveness. The advent of single-cell RNA sequencing (scRNA-seq) has enabled the comprehensive profiling of gene expression heterogeneity at the single-cell level, which has been applied to NMSC to quantify cell compositions, define states, understand tumor evolution, and discern drug resistance. In this review, we highlight the key findings, with a focus on intratumoral heterogeneity and the mechanism of drug resistance in NMSC, as revealed by scRNA-seq. Furthermore, we propose potential avenues for future research in NMSC using scRNA-seq.

Keywords: drug resistance; intratumoral heterogeneity; non-melanoma skin cancer; recurrence; scRNA-seq; single-cell RNA sequencing.

Figure 1

General workflow of scRNA-seq experiments from sequencing to data analysis. (A) General workflow of scRNA-seq experiments in NMSCs. (B) General analyses for scRNA-seq data. Data was downloaded and analyzed with the accession of GSE130973, GSE1993304, GSE144236, GSE200334, and GSE218170 from the Gene Expression Omnibus (GEO) database. NMSC, non-melanoma skin cancer; scRNA-seq, single-cell RNA sequencing; UMAP, uniform manifold approximation and projection; CNV, copy number variation.

Figure 2

Representative advances of NMSC by scRNA-seq. KCs, Keratinocytes; CAFs, Cancer-associated fibroblasts; TAMs, tumor-associated macrophages; ICI, Immune checkpoint inhibitors; TME, Tumor microenvironment; NMSC, Non-melanoma skin cancer; BCC, Basal cell carcinoma; cSCC, Cutaneous squamous cell carcinoma; MCC, Merkel cell carcinoma; EMPD, Extramammary Paget’s disease.