Investigators from the Barts Cancer Institute at Queen Mary University of London have made a groundbreaking discovery regarding the role of mitochondrial dynamics in controlling the migration of melanoma skin cancer cells, as revealed in a study published in Nature Communications. Additionally, they found that the AMP-activated protein kinase (AMPK) serves as a crucial sensor for tumor dissemination.
Eva Crosas-Molist, a researcher from Queen Mary University of London, stated:
These metastatic cells are rewiring themselves to be very efficient. 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.
The study uncovered that ATP energy derived from the mitochondria, known as the powerhouse of the cell, is indispensable for cell migration compared to glycolysis. Elongated-mesenchymal migration necessitates high levels of ATP for strong adhesion and fusion with the mitochondria.
The researchers observed that, to inhibit discoidin domain receptor 1-mediated adhesion, ATP levels decrease in the cells, activating AMPK and deactivating Myosin Phosphatase, including Myosin II, thus enabling rounded-amoeboid migration. This process allows cancer cells to detach from the original tumor and spread to different parts of the body.
Rounded-amoeboid migration facilitates more efficient movement of cells throughout the body, while mesenchymal migration tends to be slower.
Mitochondrial fission is also a part of this process, activated by AMPK. Cells undergoing rounded-amoeboid migration display higher intrinsic AMPK activation, leading to mitochondrial fragmentation. The researchers discovered that impairment of mitochondrial fusion, achieved by silencing MFN2, or induction of mitochondrial fission through AMPK, results in mitochondrial fragmentation and rounded-amoeboid migration.
Investigators have also determined that fragmented yet functional mitochondria pose a greater risk as cancer cells, primarily due to their low energy consumption and ability to migrate throughout the body.
Furthermore, investigators found that AMPK activation in low-adherent cells can enhance Myosin II-dependent three-dimensional invasion. They emphasized the need for further research on the various levels of Myosin II regulation, particularly in migrating cells, as most studies have primarily focused on the regulation of Myosin activity by Rho-associated protein kinase.
“Patients whose cancer has metastasized often face more challenging treatments and reduced chances of survival. Understanding how cancer cells travel within the body can provide valuable insights for designing interventions to prevent this in the future. The more we comprehend the processes occurring in the bodies of cancer patients, the better equipped we will be to combat the disease,” stated Dr. Ketan Patel, Chief Scientist at Cancer Research UK.
Investigators also highlighted the potential use of compounds that affect AMPK in other disease states, such as diabetes, mitochondrial disorders, and cardiovascular diseases, particularly for patients with advanced cancer.