Integrating scRNA-seq and Visium HD for the analysis of the tumor microenvironment in the progression of colorectal cancer.

Background: Colorectal cancer (CRC) development is a complex, multi-stage process, transitioning from normal to adenomatous tissue, and then to invasive carcinoma. Despite research, there's a knowledge gap on using high-resolution spatial omics to understand CRC's tumor microenvironment dynamics.

Methods: We used single-cell transcriptomics to study major biological changes and cell interactions in CRC progression. Additionally, high-resolution spatial transcriptomics helped us examine the spatial distribution of cells with significant pathway changes, offering insights into the tumor microenvironment's development throughout CRC stages.

Results: In the progression of CRC, plasma cells, neutrophils, and fibroblasts exhibit the most significant changes in hallmark pathways, while epithelial cells show the most pronounced alterations in metabolic pathways. We also identified a population of NOTUM + epithelial cells and IGHG1/3 + plasma cells that are concentrated at the boundary between normal tissue and adenomas. Pathway analysis further suggests that these NOTUM + cells activate numerous cancer-related pathways, despite the absence of significant pathological morphological changes. Additionally, we conducted a targeted drug prediction analysis to identify potential therapeutic agents for NOTUM-expressing epithelial cells.

Conclusions: Analyzing scRNA-seq and Visium HD data, we found that IGHG1/3 + plasma cells and tumor-associated neutrophil (TANs) may significantly affect colorectal tissue transformation from normal to adenoma and carcinoma. These cells are concentrated at the transition between normal and adenomatous tissue. We also found NOTUM-expressing cells at the edge of normal and adenomatous areas, possibly indicating a morphological transition as normal cells evolve into adenoma cells.