Neutrophil extracellular traps regulate LDHA expression to promote colorectal cancer liver metastasis

Metastasis is the most common cause of colorectal cancer (CRC)-related death. Neutrophil extracellular traps (NETs) promote tumor progression and distant metastasis. This study aimed to explore the role of NETs in CRC liver metastasis. Through analysis of publicly available single-cell transcriptome sequencing databases, in vitro experiments and nude mouse liver xenograft model experiments, we revealed that NETs promote CRC metastatic progression. Using scRNA-Seq technology, we showed that NETs marker expression was higher in metastatic lesions than in primary tumors. NET marker expression was high in colorectal cancer tissues and correlated with advanced tumor pathological grade. In addition, treatment with NETs enhanced the proliferation, migration and invasion of CRC cells in vitro by inducing EMT, as indicated by downregulation of E-cadherin and upregulation of N-cadherin and Vimentin. Cell-cell communication analysis revealed that NETs are related to the PI3K/AKT pathway and regulate the expression of LDHA, a key enzyme in glucose metabolism. In vitro, treatment with NETs promoted LDHA production and cell invasion and migration in CRC, while knockdown of LDHA suppressed EMT. Further, inhibition of LDHA expression or NET formation effectively inhibited NET-induced liver metastasis. In summary, this study elucidates the mechanism by which NETs regulate LDHA expression to promote CRC liver metastasis.