Colorectal cancer exosomes induce lymphatic network remodeling in lymph nodes

The lymphatic network remodeling may guide tumor metastasis in a sentinel lymph node (SLN). Although tumor-derived exosomes have been demonstrated to modify the microenvironment in adjacent organs and initiate a premetastatic niche, their influence on the lymphatic network in SLNs has not been explained. Here, we show that CT26 cell exosomes (Exo) promote the proliferation of lymphatic endothelial cells and the formation of lymphatic network in SLN, facilitating the SLN metastasis of colorectal cancer (CRC). Uptake of Exo by macrophages promoted VEGFC secretion both in vivo and in vitro. Exo increased the frequency of F4/80⁺ macrophages in the SLN. Macrophage ablation by clodrosome prevented the exosomal effect on lymphatic network remodeling and SLN metastasis. Exosomal IRF-2 was highly expressed in serum exosomes isolated from CRC patients with LN metastasis relative to patients without LN metastasis and healthy controls. Mechanistically, exosomal IRF-2 induced the release of VEGFC by macrophages. An IRF-2 knockdown attenuated the lymphatic network remodeling in the SLN and suppressed the SLN metastasis. Our data suggest that exosomal IRF-2 remodels the lymphatic network in an SLN and may predict the development of CRC LN metastases.