Exosomal integrin αvβ3 derived from colorectal cancer promotes the liver pre-metastatic niche formation by inducing cancer-associated fibroblasts activation

The formation of the liver pre-metastatic niche (PMN) is a critical factor in the development of colorectal cancer liver metastasis (CRLM), so understanding the mechanism of the liver PMN is crucial for the prevention and treatment of CRLM. Hepatic stellate cells (HSCs) can promote CRLM by forming cancer-associated fibroblasts (CAFs), but the mechanism remains unclear. In this study, we found that integrin αvβ3 is associated with CRLM and the poor clinical prognosis. Exosomal integrin αvβ3 derived from CRC can target HSCs via fibronectin to mediate their activation. We further explored the mechanism and found that exosomal integrin αvβ3 activates the MEK-ERK signaling pathway through the vitronectin-Integrin αvβ3-FAK axis, thereby promoting HSCs activation. After HSCs become CAFs, they promote the formation of the PMN through EMT, angiogenesis, and inflammatory factors, thereby promoting CRLM. In summary, this study clarifies that exosomal integrin αvβ3 derived from CRC can promote the formation of liver PMN by mediating HSC activation into CAFs, providing a novel therapeutic strategy for the prevention and treatment of CRLM.