Although previous studies have provided insights into the genetic and transcriptional changes that characterize malignancy in cancers, premalignant lesions are not described to the same extent. Thus, limited data are available on phenotypic changes during progression from benign, to precancerous and cancerous lesions. Becker et al. used colorectal cancer (CRC) as a system for studying stages of malignant transformation, as CRC follows a well-defined normal–atypical–carcinoma progression including the formation of precancerous polyps. Single-nuclei transcriptomes (using single-nucleus RNA sequencing (snRNA-seq)) and epigenomes (using single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq)) from healthy colon, polyps and CRC were profiled from 81 samples across 15 donors. Cell-type analysis revealed enrichment of regulatory T cells and T cell exhaustion in polyps and CRC, and a cluster of cancer-associated fibroblasts (CAFs) derived almost exclusively from CRC. RNA analysis of CAFs provided a gene expression profile distinct from fibroblasts in normal colon or polyps. Analysis of epithelial cells revealed increased stem-like properties in polyps and CRC compared with healthy colon. Furthermore, the authors classified the aberrant gene expression and regulatory programs of these stem-like cells along a continuum from normal to cancerous tissue, and tracked changes in gene expression from normal colon to cancer. In addition, changes in cell-type composition were observed along this malignancy continuum, and DNA methylation analysis across progression stages showed correlation with chromatin accessibility. The findings from this study highlight potential methods of staging polyps and assessing clinical risk using various molecular features; however, thorough future clinical investigation is necessary.
Original reference: Nat. Genet. 54, 985–995 (2022)
This is a preview of subscription content, access via your institution
