2. Academic Validation
  3. Loss of Myo19 increases metastasis by enhancing microenvironmental ROS gradient and chemotaxis

Loss of Myo19 increases metastasis by enhancing microenvironmental ROS gradient and chemotaxis

  • EMBO Rep. 2024 Jan 26. doi: 10.1038/s44319-023-00052-y.
Xiaoyu Ren # 1,  Peng Shi # 2 3,  Jing Su 4,  Tonghua Wei 1,  Jiayi Li 1,  Yiping Hu 1,  Congying Wu 5 6
Affiliations

Affiliations

  • 1 Institute of Systems Biomedicine, Peking University Health Science Center, Key Laboratory of Tumor Systems Biology, Beijing, 100191, China.
  • 2 Institute of Systems Biomedicine, Peking University Health Science Center, Key Laboratory of Tumor Systems Biology, Beijing, 100191, China. peng@bjmu.edu.cn.
  • 3 International Cancer Institute, Peking University, Beijing, 100191, China. peng@bjmu.edu.cn.
  • 4 Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
  • 5 Institute of Systems Biomedicine, Peking University Health Science Center, Key Laboratory of Tumor Systems Biology, Beijing, 100191, China. congyingwu@hsc.pku.edu.cn.
  • 6 International Cancer Institute, Peking University, Beijing, 100191, China. congyingwu@hsc.pku.edu.cn.
  • # Contributed equally.
PMID: 38279020 DOI: 10.1038/s44319-023-00052-y
Abstract

Tumor metastasis involves cells migrating directionally in response to external chemical signals. Reactive Oxygen Species (ROS) in the form of H2O2 has been demonstrated as a chemoattractant for neutrophils but its spatial characteristics in tumor microenvironment and potential role in tumor cell dissemination remain unknown. Here we investigate the spatial ROS distribution in 3D tumor spheroids and identify a ROS concentration gradient in spheroid periphery, which projects into a H2O2 gradient in tumor microenvironment. We further reveal the role of H2O2 gradient to induce chemotaxis of tumor cells by activating Src and subsequently inhibiting RhoA. Finally, we observe that the absence of mitochondria cristae remodeling proteins including the mitochondria-localized actin motor Myosin 19 (Myo19) enhances ROS gradient and promotes tumor dissemination. Myo19 downregulation is seen in many tumors, and Myo19 expression is negatively associated with tumor metastasis in vivo. Together, our study reveals the chemoattractant role of tumor microenvironmental ROS and implies the potential impact of mitochondria cristae disorganization on tumor invasion and metastasis.

Keywords

Chemotaxis; Mitochondria; Myo19; ROS Gradient; Tumor Metastasis.

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