Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway

Pattern‐recognition receptors (PRRs) have been shown to promote tumour metastasis via sensing tumour cell‐derived small extracellular vesicles (EVs). Nucleotide‐binding oligomerisation domain 1 (NOD1), a cytoplasmic PRR, plays a role in colorectal cancer (CRC) by detecting bacterial products. However, the precise mechanisms underlying the effects of NOD1, following identification of CRC cell‐derived EVs (CRC‐EVs), to potentiate CRC liver metastasis (CRC‐LM), remain poorly understood. Here, we demonstrate that CRC‐EVs activate NOD1 in macrophages to initiate secretion of inflammatory cytokines and chemokines. NOD1‐activated macrophages also promote CRC cell migration, while in a murine model of liver metastasis (LM), NOD1‐deficient mice exhibit reduced metastasis following CRC‐EV treatment. Furthermore, cell division cycle 42 (CDC42), a small Rho guanosine‐5′‐triphosphate (GTP)ase, is delivered by CRC‐EVs into macrophages where it activates NOD1. In addition, EVs from the plasma of patients with CRC‐LM mediate NOD1 activation in human peripheral blood mononuclear cells. Moreover, high NOD1 expression in tumour tissues is associated with poor prognosis of CRC‐LM. Our findings suggest that CRC‐EVs activate NOD1 to promote tumour metastasis, thus, NOD1 may serve as a potential target in the diagnosis and treatment of CRC‐LM.