Single‐cell multi‐omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying CRC‐unique features

: Colorectal cancer (CRC) arises in the colorectal tissue driven by genetic disorder or the accumulation of somatic mutations, leading to abnormal epithelial cell growth. In this study, we employed single-nucleus multi-omics analysis, including single-nucleus RNA-seq and single-nucleus ATAC-seq, on over 100,000 high-quality nuclei to investigate the molecular landscape of both primary tissue and patient-derived organoids (PDOs). Our analysis showed that normal PDOs (N-PDOs) derived from tissue adjacent to tumors replicate the cellular composition and differentiation trajectory of colorectal crypts. In contrast, tumor PDOs (T-PDOs) showed patient-specific transcriptomic and epigenomic heterogeneity yet consistently maintained a stem cell-like state. T-PDOs retained the somatic mutation profile of the primary tumor while also exhibiting de novo mutations not detected in either the primary tumor or N-PDOs. Notably, inferred cell-cell interaction analysis highlighted the activin signaling pathway as a potential unique feature of fibroblast-epithelial interactions within the tumor microenvironment. This study provides a comprehensive view of the transition from normal to malignant colorectal epithelium and underscores the utility of PDOs as a faithful model for capturing both conserved and patient-specific features of colorectal cancer.