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. Overall design: 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.