Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities
Meng Ya-Ming, Jiang Xue, Zhao Xinbao, Meng Qiong, Wu Sangqing, Chen Yitian, Kong Xiangzhan, Qiu Xiaoyi, Su Liangping, Huang Cheng, Wang Minghui, Liu Chao, Wong Ping-Pui
Journal：Nature Communications
IF：14.92
DOI：10.1038/s41467-021-26259-y
PMID：
Published：2021-10-14
research field：肿瘤学细胞生物学代谢癌症生物学遗传学与基因组学
Abstract
Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role. Pericyte-endothelial cells interaction defines tumor vasculature and has implications in tumorigenesis development and therapy efficacy. Here, the authors show that hexokinase 2- driven glycolysis activates ROCK1-MLC2 mediated contractility in pericytes leading to tumor blood vessel abnormality.
本文使用的Yeasen产品
