Nidogen 1-enriched extracellular vesicles promote liver metastasis by inducing EMT and activating stellate cells

The liver is frequently affected by metastasis in colorectal cancer patients; however, the precise interaction between the liver microenvironment and metastatic colorectal cancer cells remains elusive. Our study revealed that NID1, present in extracellular vesicles (EVs) derived from metastatic colorectal cancer, plays a pivotal role in promoting colorectal cancer liver metastasis (CRLM). EV-NID1 facilitates epithelial-mesenchymal transition (EMT) in colorectal cancer cells by modulating EMT-associated genes. Moreover, EV-NID1 activates hepatic stellate cells (HSCs), which in turn stimulate neutrophil infiltration and induce the formation of neutrophil-trapping networks (NETs) within the hepatic metastatic microenvironment via interleukin-11 (IL-11) secretion. This process ultimately reshapes the tumor microenvironment (TME) and fosters the establishment of a metastatic niche conducive to CRLM. Notably, targeted inhibition of IL-11 signaling via anti-IL-11 monoclonal antibodies effectively suppressed EV-NID1-induced liver metastasis in a murine model. In summary, our findings elucidate the mechanism underlying EV-NID1-mediated regulation of CRLM, identifying a promising therapeutic target for intervention in this disease.