Loss of Myo19 Increases Metastasis by Enhancing Microenvironmental ROS Gradient and Chemotaxis

Loss of Myo19 Increases Metastasis by Enhancing Microenvironmental ROS Gradient and Chemotaxis

Dysregulated cellular metabolism, elevated reactive oxygen species (ROS), and loss of cristae integrity have all been associated with tumor progression and in some cases enhanced metastasis.  Ren et al. identify the mitochondria-localized actin motor Myosin 19 (Myo19) as an important regulator of ROS levels in spheroid cancer models.  The group performed preliminary immunohistochemistry studies on breast carcinoma samples and found a correlation between low Myo19 levels and a high incidence of metastasis in these patient samples.  Utilizing mouse models, the group produced supporting results that Myo19 knockdown led to higher tumor invasiveness.  The group then turned to a spheroid model to assess the mechanisms responsible for Myo19’s role in cancer invasion.  These studies confirmed that Myo19 loss resulted in elevated ROS levels; interestingly, the ROS levels weren’t distributed equally throughout the spheroid, rather it was higher in the outer shell while remaining lower in the middle layer.  Live cell imaging was performed to analyze the invasiveness of cells in response to ROS gradients, and they found that creating a ROS gradient through layering Myo19 KO cells on top of wild-type cells promoted spheroid cancer cell invasion.  This mechanism of chemotaxis by tumor cells was replicated with an H2O2 gradient in a Boyden chamber system providing further evidence of its importance to cancer cell invasion.  Finally, the group identified Src as a key redox sensor in these cancer cells and showed that suppressing Src activation blunted H2O2 chemotaxis.  Furthermore, they showed that Src activation led to RhoA inhibition, and treatment with a RhoA inhibitor was sufficient to abolish H2O2 chemotaxis.  Collectively, the group identified key regulators linking the potential of cristae dysfunction to enhanced ROS gradients and the promotion of tumor invasion.  Cytoskeleton Inc.’s RhoA Activator (Cat. # CN03) and RhoA Pull-down Activation Assay (Cat. # BK036) were critical tools for investigating the role of RhoA in these studies. 

Additional Related Product:

Rhotekin-RBD Beads (Binds Active Rho Proteins) (Cat # RT02)


Figure Legend: Schematic showing how Myo19 loss can promote ROS gradients in the periphery of spheroids that induce metastasis through RhoA inhibition via Src activation.