Pericytes promote metastasis by regulating tumor local vascular tone and hemodynamics

作者：Xiaobo Li, Sishan Yan, Xiaoyu Wu, Qun Miao, Dong Zhang, Dong Zhang, Wenfeng Mai, Shuai Han, Zhongshun Tang, Mingfang Ye, Shuo Zhang, Ji‐an Wei, Jinghua Pan, Dandan Huang, Shenghui Qiu, Zhan Zhao, Xiaotong Zhong, Maohua Huang, Ming Qi, Junqiu Zhang, Chenran Wang, Jingwen Xie, Sheng Wang, Oscar Junhong Luo, Dongmei Zhang, Dongmei Zhang, Wen‐Cai Ye, Minfeng Chen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-62475-6 · 被引用次数：7 · 研究领域：Angiogenesis and VEGF in Cancer、Cancer Cells and Metastasis、Extracellular vesicles in disease

Hemodynamics are important for survival and extravasation of circulating tumor cells, whereas the effects of hemodynamics on tumor cell intravasation remain mostly unknown. Here, we show that colorectal cancer patients with liver metastasis are characterized by increased diameter and blood flow in the primary tumor compared with non-metastatic patients. A subpopulation of NKX2-3high tumor pericytes (TPCs) in the primary tumor is associated with hematogenous metastasis of patients. Mechanistically, long noncoding RNA NEAT1-enriched extracellular vesicles induce NKX2-3 upregulation in TPCs. NKX2-3 suppresses calcium influx in TPCs via PDE1C/cAMP/PKA signaling axis, inducing tumor vasodilation and increasing blood flux and vascular leakage. Genetic deletion of Nkx2-3 or pharmacological blocking the transcriptional activity of NKX2-3 in TPCs with designed peptide induce tumor local vasoconstriction and decrease blood flow to mitigate tumor metastasis. These findings reveal that TPCs-regulated vasodilation and hemodynamics facilitate tumor metastasis, and provide a potential prognostic marker and therapeutic strategy for tumor metastasis. Tumor pericytes are located surrounding blood vessels, and can regulate tumor vascular structure. Here, the authors discover that a subpopulation of NKX2-3 high tumor pericytes modulates vasodilation and hemodynamics to promote metastasis.