The following is the summary of “Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer” published in the January 2023 issue of Cellular and Molecular Gastroenterology and Hepatology by Zhou, et al.

Serrated lesions (SLs) such as hyperplastic polyps (HP), sessile serrated lesions (SSLs), traditional serrated adenomas (TSAs), and SSLs with dysplasia (SSLDs) account for about one-third of all colorectal cancers and progress more rapidly than the conventional adenoma-carcinoma pathway. In SLs, researchers aimed to use the single-cell environment to illustrate the underlying, as-yet-undefined molecular and immunological changes. Therefore, in comparison to 3 normal colonic tissues, we sequenced the RNA of individual cells from 16 SLs (4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs).

In all, 60,568 healthy cells were harvested. As well as the upregulation of tumor-promoting SerpinB6 that regulated ROS level, 2 epithelial clusters with redox imbalance in SLs were observed. There were clear molecular differences between the epithelial clusters of SSL and TSA. Epithelium associated with SSL showed overexpressed proliferative markers and Notch pathway activation, whereas epithelium associated with TSA displayed Paneth cell metaplasia and aberrant lysozyme expression. Enhanced cytotoxic activity of CD8+ T cells was observed in SLs, with the increase likely attributable to a higher proportion of CD103+CD8+ tissue-resident memory T cells, whose activity is controlled by retinoic acid metabolism. 

Although the SL microenvironment was highly immune-activated, immunosuppressive cells (regulatory T cells, anti-inflammatory macrophages, MDK+ IgA+ plasma cells, MMP11-secreting PDGFRA+ fibroblasts) emerged early on and accumulated in SSLD. Changes of a fundamental nature occur in the serrated pathway’s epithelial, immune, and stromal components. Potential future molecular subtypes of SLs and immune therapies.