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

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Tumor metastasis involves directed cell migration influenced by chemical signals.
• Hydrogen peroxide (H2O2) is a known neutrophil chemoattractant, but its role in tumor cell dissemination is unclear.
• The spatial distribution of reactive oxygen species (ROS) in the tumor microenvironment is not well understood.

Purpose of the Study:

• To investigate the spatial distribution of ROS in 3D tumor spheroids.
• To determine the role of H2O2 gradients in tumor cell chemotaxis and metastasis.
• To explore the function of mitochondria and Myosin 19 (Myo19) in regulating ROS gradients and tumor dissemination.

Main Methods:

• 3D tumor spheroid models were used to analyze ROS distribution.
• Chemotaxis assays were performed to assess tumor cell migration in response to H2O2 gradients.
• Molecular pathways involving Src and RhoA were investigated.
• The role of mitochondria and Myo19 in ROS production and tumor cell dissemination was examined.

Main Results:

• A ROS concentration gradient, specifically H2O2, was identified in the periphery of 3D tumor spheroids and the tumor microenvironment.
• The H2O2 gradient induces tumor cell chemotaxis by activating Src and inhibiting RhoA.
• Absence of mitochondria cristae remodeling proteins, like Myo19, enhances the ROS gradient and promotes tumor dissemination.
• Myo19 downregulation correlates with increased tumor metastasis in vivo.

Conclusions:

• Tumor microenvironmental ROS, particularly H2O2, function as chemoattractants for tumor cells.
• Mitochondrial dysfunction, specifically impaired cristae remodeling due to proteins like Myo19, can enhance ROS gradients and promote tumor invasion and metastasis.
• Myo19 downregulation is observed in various tumors and is negatively associated with metastasis, suggesting its potential as a therapeutic target.