The protein navigating melanoma metastasis

A protein critical to melanoma cell metastasis has been discovered, offering strategies to impede cancer spread throughout the body.

In a recent study, researchers from the Center for Genomic Regulation (Barcelona, Spain) have discovered the protein responsible for steering melanoma cells as they spread to new areas of the body. This work has implications for impeding metastasis as they develop ways to interfere with this critical protein.

Melanoma is responsible for almost 60,000 deaths worldwide every year, despite only making up a fraction of skin cancer cases. While localized melanoma has a 5-year survival rate of 99%, metastatic melanoma has a 5-year survival rate of just 35%. This difference has urged researchers to investigate how malignant cells metastasize in the hopes of identifying an effective target to stop cancer spread throughout the body.

The RNA-binding protein eukaryotic translation-initiation factor 2A (eIF2A) is an alternative translation initiation factor involved in activating ribosomes to launch protein synthesis, jumping into action when a cell is under stress. Translation regulation plays a significant role in cancer progression; many previous studies have linked eIF2A to cancer and a previous screen by the team demonstrated the potential involvement of eIF2A in the metastatic progression of melanoma.

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To explore the connection between eIF2A and metastasis, the researchers compared how matched human skin cell lines that differed only in their metastatic potential reacted to decreased levels of eIF2A. In the metastatic cells, the researchers observed that the tumor spheres stopped growing and cell migration along a scratch in a culture dish slowed significantly. However, unexpectedly, protein synthesis remained mostly unaffected in both lines, suggesting that there must be an alternative role for the protein.

Using T4 polynucleotide kinase assays, they were able to determine that eIF2A binds RNA similarly in both cell lines and eIF2A. Next, they turned their attention to the RNA bound by each cell line – and how eIF2A affected binding – leveraging a series of immunoprecipitation and sequencing techniques. Using liquid chromatography–tandem mass spectrometry, they discovered that many of the RNA bound to eIF2A in the cancer line were components of the centrosome, a molecular structure that arranges microtubules and orients cells during movement. In the absence of eIF2A, the centrosome often pointed the wrong way as cells tried to advance.

They identified that eIF2A’s tail played a key role in maintaining the centrosome in malignant cells and generating migration power. When this tail was trimmed, the cells’ movement was affected, offering a potential target for impeding metastatic cancer cells.

Because of the cell’s dependence on eIF2A for tumoral characteristics, such as migration and spheroid growth, only emerges after malignant transformation, the researchers believe that there may be a specific therapeutic window that could be taken advantage of to spare healthy tissues. However, more work is needed to determine how disrupting the protein’s behavior 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,” concluded corresponding author Fátima Gebauer.