Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Yuyuan Zhang
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Anning Zuo
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Yuhao Ba
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Shutong Liu
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Jingqi Chen
Shuaixi Yang
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University
Siyuan Weng
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Yukang Chen
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Hui Xu
Peng Luo
Quan Cheng
Department of Neurosurgery, Xiangya Hospital, Central South University
Bufu Tang
Department of Radiation Oncology, Zhongshan Hospital, Fudan University
Benyu Liu
Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University
Chuhan Zhang
Department of Oncology, The First Affiliated Hospital of Zhengzhou University
Jingkuan Yang
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Xinwei Han
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
Zaoqu Liu
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University