Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities

Ya-Ming Meng, Xue Jiang, Xinbao Zhao, Qiong Meng, Sangqing Wu, Yitian Chen, Xiangzhan Kong, Xiaoyi Qiu, Liangping Su, Cheng Huang, Minghui Wang, Chao Liu and Ping-Pui Wong ()
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Ya-Ming Meng: Sun Yat-sen University
Xue Jiang: Sun Yat-sen University
Xinbao Zhao: Sun Yat-sen University
Qiong Meng: Sun Yat-sen University
Sangqing Wu: Sun Yat-sen University
Yitian Chen: Sun Yat-sen University
Xiangzhan Kong: Sun Yat-sen University
Xiaoyi Qiu: Sun Yat-sen University
Liangping Su: Sun Yat-sen University
Cheng Huang: Sun Yat-sen University
Minghui Wang: Sun Yat-sen University
Chao Liu: Sun Yat-sen University
Ping-Pui Wong: Sun Yat-sen University

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26259-y

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