Single-cell transcriptomic profiling of colorectal cancer brain metastasis

BACKGROUND: Brain metastasis from colorectal cancer (CRC) remains a highly lethal disease. However, the molecular mechanisms driving CRC brain metastasis are not fully characterized. METHODS: Employing single-cell RNA sequencing (scRNA-seq), we delineated the cellular atlas of a resected CRC brain metastasis specimen and particularly focused on the tumor cell compartment. RESULTS: Our scRNA-seq analysis profiled 4,748 high-quality single cells from a CRC brain metastasis sample. Tumor cells constituted the dominant population. Within the immune compartment, myeloid cells, including macrophages and monocytes, represented the predominant components of the metastatic microenvironment. In addition, key elements of the blood-tumor barrier, such as endothelial cells and pericytes, were characterized and implicated in brain metastasis. Tumor cells showed phenotypic plasticity, with transcriptional dynamics consistent with a mesenchymal-to-epithelial transition. Notably, a highly proliferative tumor cell subset with elevated KMT2B expression was identified. Functional analyses demonstrated that KMT2B depletion significantly impaired CRC cell proliferation and migration. Mechanistically, KMT2B promoted metastatic potential partly by upregulating MEX3A expression. Furthermore, high expression levels of KMT2B and MEX3A were associated with poor prognosis in both CRC and pan-cancer patients. CONCLUSION: Collectively, this study identifies KMT2B as a potential driver of CRC brain metastasis and highlights it as a candidate therapeutic target for CRC treatment.