Highly-metastatic colorectal cancer cell released Nidogen 1-Enriched Extracellular Vesicles promote liver metastasis by activating hepatic stellate cells and forming the neutrophilextracellulartraps

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 reveals 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 extracellular traps (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 using anti-IL-11 monoclonal antibodies effectively suppresses EV-NID1-induced liver metastasis in a murine model. In summary, our findings elucidate the mechanism underlying EV-NID1-mediated regulation of CRLM, presenting a promising therapeutic target for intervention in this disease. 1. In order to study the characteristics of metastatic colorectal cancer cells, we screened high metastatic cell lines by spleen injection of SW480 cells, and through three rounds of screening, we obtained a high metastatic colorectal cancer cell line named SW480-LM3, and the parental cells were SW480-P;2.To investigate the effect of exosome-derived NID1 protein on hepatic stellate cells LX-2, hepatic stellate cells were incubated for 48 hours using exosomes containing NID1, designated EV-XP-NID1-LX-2, and control EV-XP-LX-2;3.To investigate the effect of the exosomal pathway on epithelial mesenchymal transition in colorectal cancer cell lines, SW480 colorectal cancer cell line overexpressing NID1, named LV5-NID1, was treated for 72 hours using GW4869, and the control group was LV5.