Researchers have discovered a protein which is critical for steering melanoma cancer cells as they spread throughout the body. The malignant cells become dependent on this protein to migrate, pointing to new strategies for impeding metastasis.
The protein eIF2A is generally thought to spring into action when a cell is under stress, helping ribosomes launch protein synthesis. But according to a study published today in the journal Science Advances, eIF2A has a completely different role in melanoma, helping cancerous cells control movement.
"Malignant cells that metastasize need to make their way through tissues in order to invade proximal or distant organs. Targeting eIF2A could be a new strategy to impede melanoma breaking free and seeding tumours elsewhere," says Dr. Fátima Gebauer, corresponding author of the study and researcher at the Centre for Genomic Regulation (CRG) in Barcelona.
Despite accounting for only a fraction of skin cancer cases, melanoma kills almost 60,000 people worldwide each year. The five-year survival rate for localised melanoma is around 99%, while it is significantly lower for metastatic melanoma, around 35% for distant spread. Understanding how malignant cells metastasise is crucial to improve healthcare outcomes.
Working with a pair of matched human skin cell lines differing only in their metastatic potential, the team dialled down the effects of eIF2A. In cancer cells, three-dimensional tumour spheres stopped growing and migration across a scratch in the culture dish slowed dramatically. Yet protein manufacturing was barely affected, overturning the idea that eIF2A's launches protein synthesis.
To hunt for an alternative role, the researchers pulled eIF2A out of the cell using a molecular fishing line and catalogued which protein partners it was attached to. Many turned out to be components of the centrosome, a molecular structure which arranges microtubules and orients cells during movement. When eIF2A was absent, the centrosome often pointed the wrong way as cells tried to advance.
Further experiments revealed eIF2A works to preserve parts of the centrosome so it points the cell in the right direction during movement. The protein's tail is critical for the cell's migration power. Trimming the tail affected the cell's ability to move and could be a potential drug-friendly target.
"The tail behaves like scaffolding cement, holding key parts of the melanoma's cellular compass in place so that malignant cells can navigate their way out of the primary tumour," says Dr. Jennifer Jungfleisch, first author of the study.
The authors of the study note that eIF2A dependence only emerges after malignant transformation, suggesting a therapeutic window that might spare healthy tissues. However, more work needs to be done to see how disrupting the protein's behaviour works in tissues and animal models.
"In this field, many potential therapeutic targets prove either redundant or essential to normal cells, but the discovery of a protein that quietly makes itself indispensable only when cells become metastatic could be a rare catch. Any potential vulnerability counts," concludes Dr. Gebauer.
