Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation
Menée in vitro et à l'aide d'une xénogreffe de cancer colorectal sur un modèle murin, cette étude met en évidence un mécanisme par lequel la sémaphorine 3C sécrétée par les fibroblastes CAF favorise le développement de métastases hépatiques en activant la voie de signalisation de la kinase MAPK via le récepteur NRP2
Liver metastasis remains the predominant cause of mortality in patients with colorectal cancer (CRC). Nevertheless, the mechanisms underlying the initiation of colorectal cancer liver metastasis remain poorly elucidated. During the metastatic process of CRC cells from the primary site to the liver, we performed time-resolved analyses and identified a subset of tumor cells spatially located in the primary tumor and temporally distributed in the early stages of liver metastasis. These cells were termed liver metastasis-initiating cells (LMICs). LMICs exhibit high stemness, low proliferation, active interaction with surrounding stromal components, and a close association with liver metastasis. Notably, we found significant interactions between cancer-associated fibroblasts (CAFs) and LMICs via the SEMA3C–NRP2 receptor–ligand pair. Further in vivo and in vitro experiments confirmed that CAF-secreted SEMA3C could bind to the NRP2 receptor, which activates the MAPK pathway and promotes colorectal cancer liver metastasis. Our findings suggest potential therapeutic strategies for the early prevention of colorectal cancer liver metastasis.
Proceedings of the National Academy of Sciences , résumé, 2025