Dissecting the heterogeneities of the tumor microenvironment between metastatic and nonmetastatic primary colorectal cancer patients by single-cell RNA sequencing.

AIMS: One of the main factors hampering the long-term prognosis of colorectal cancer (CRC) patients is distant metastasis. However, the driving factors of CRC metastasis have not been clarified at the single-cell level, which limits the in-depth study of accurate prediction and prevention of CRC metastasis to improve the prognosis.

MATERIALS AND METHODS: Heterogeneities in the tumor microenvironment (TME) between metastatic and nonmetastatic CRC were investigated by single-cell RNA (scRNA) sequencing data. In detail, 50,462 single cells from 20 primary CRC samples, including 40,910 cells from nonmetastatic CRC (M0 group) and 9552 cells from metastatic CRC (M1 group), were systematically analyzed in this study.

KEY FINDINGS: Based on the single-cell atlas, we revealed that cancer cells and fibroblasts accounted for relatively high proportions in metastatic CRC compared with nonmetastatic CRC. Moreover, two specific cancer cell subtypes (FGGY+ SLC6A6+ and IGFBP3+ KLK7+ cancer cells) and three specific fibroblast subtypes (ADAMTS6+ CAPG+ , PIM1+ SGK1+ and CA9+ UPP1+ fibroblasts) in metastatic CRC were identified. The functional and differentiation characteristics of these specific cell subclusters were elucidated by enrichment and trajectory analyses.

SIGNIFICANCE: These results provide fundamental knowledge for future in-depth research to screen effective methods and drugs to predict and prevent CRC metastasis to improve prognosis.