Mitochondrial Fragmentation Plays Key Role in Spreading of Melanoma Cancer Cells

Investigators from the Barts Cancer Institute at Queen Mary University of London have discovered that mitochondrial dynamics control migration of melanoma skin cancer cells, according to the results of a study published in Nature Communications.¹

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They also discovered that AMP-activated protein kinase (AMPK) is an essential sensor for tumor dissemination.¹

“These metastatic cells are rewiring themselves to be very efficient,” Eva Crosas-Molist from the Queen Mary University of London, said in a statement. “They only need low levels of energy to move, which helps them to survive in the potentially stressful environments they are migrating to, where there may be a lack of nutrients or oxygen.”²

For cell migration, it was found that ATP energy from the mitochondria, the powerhouse of the cell, was essential compared to glycolysis. When elongated-mesenchymal migration is present, the cells require high levels of APT to ensure strong adhesion and fuse to the mitochondria.¹

The study authors found that to prevent discoidin domain receptor 1-mediated adhesion, the APT level drops in the cells, which activates AMPK and inactivates Myosin Phosphatase, including Myosin II rounded-amoeboid migration. This allows the cancer cell to break away from the origin tumor and travel to various parts of the body.¹

Rounded-amoeboid migration allows for better movement of the cell through the body, whereas mesenchymal migration typically has slower migration speeds.¹

Part of the process also includes mitochondrial fission, which is activated by AMPK. The rounded-amoeboid migrating cells display higher intrinsic AMPK activation, thus resulting in fragmenting mitochondria. Investigators found that the impairment of mitochondrial fusion due to silencing MFN2 or inducting mitochondrial fission due to AMPK lead to the mitochondrial fragmentation and rounded amoeboid migration.¹

Investigators also found that fragmented but functional mitochondria pose a greater danger as cancer cells, due to the low amount of energy usage and ability to transport throughout the body.¹

Investigators added that AMPK activation in low adherent cells can increase Myosin II-dependent 3-dimensial invasion. They stated that most studies focus directly on the regulation of Myosin activity by Rho-associated protein kinase. Investigators noted that further research is needed on the different levels of Myosin II regulation, specifically in migrating cells.¹

“Patients whose cancer has spread often face tougher treatments and lower chances of survival. These insights about how cancer cells travel around the body could be incredibly valuable for designing interventions to prevent this in the future. The more we know about what’s happening in the bodies of people with cancer, the greater our ability to tackle it will be,” Ketan Patel, PhD, chief scientist at Cancer Research UK, said in the statement.²

Investigators also noted the usage of compounds that affect AMPK in other disease states, such as diabetes, mitochondrial disease, and cardiovascular disease, especially in patients with advanced cancer.¹

References

1. Crosas-Molist E, Graziani V, Maiques O, Pandya P, et al. AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration. Nat Commun. 2023;14(1):2740. doi:10.1038/s41467-023-38292-0
2. Skin cancer rewires its energy systems to spread more efficiently. News release. EurekAlert. May 25, 2023. Accessed June 2, 2023. https://www.eurekalert.org/news-releases/990448