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

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Listed:
  • Ya-Ming Meng

    (Sun Yat-sen University
    The Third Affiliated Hospital of Guangzhou Medical University
    Sun Yat-sen University)

  • Xue Jiang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Xinbao Zhao

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Qiong Meng

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Sangqing Wu

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Yitian Chen

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Xiangzhan Kong

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Xiaoyi Qiu

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Liangping Su

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Cheng Huang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Minghui Wang

    (Sun Yat-sen University)

  • Chao Liu

    (Sun Yat-sen University)

  • Ping-Pui Wong

    (Sun Yat-sen University
    Sun Yat-sen University)

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.

Suggested Citation

  • 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 & Ping-Pui Wong, 2021. "Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26259-y
    DOI: 10.1038/s41467-021-26259-y
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    Cited by:

    1. Lei-Bo Xu & Yu-Fei Qin & Liangping Su & Cheng Huang & Qiuping Xu & Rui Zhang & Xiang-De Shi & Ruipu Sun & Jiali Chen & Zhixiao Song & Xue Jiang & Lihuan Shang & Gang Xiao & Xiangzhan Kong & Chao Liu &, 2023. "Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Sara G. Romeo & Ilaria Secco & Edoardo Schneider & Christina M. Reumiller & Celio X. C. Santos & Anna Zoccarato & Vishal Musale & Aman Pooni & Xiaoke Yin & Konstantinos Theofilatos & Silvia Cellone Tr, 2023. "Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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