More than 40 melanoma-specific genes determine disease aggressiveness

Researchers have discovered more than 40 genes that predict the level of aggressiveness of melanoma and that distinguish it from other cancers with a poor prognosis. This discovery will help to identify unique aspects of melanoma that could contribute to determine the risk of developing metastasis in patients with this disease.

What is the function of these genes? The factors that are increased in melanoma are involved in forming vesicles called endosomes. Endosomes are machinery that tumor cells, via a process called endocytosis, can use to incorporate components into their environment and obtain energy by degrading them via autodigestion or autophagy. Autophagy is also used for self-cleaning to eliminate other proteins as well as damaged or unneeded cellular components.

Among all the genes that control endocytosis, the authors of the study focused specifically on RAB7, which is highly expressed in melanoma cells. After more than 6 years of research, the research team, led by María Soengas, MD, PhD, head of the Melanoma Group at the Spanish National Cancer Research Centre (CNIO) in Madrid, Spain, showed that RAB7 acts as an orchestra director, determining the fate of melanoma cells.

At high concentrations of RAB7, cellular autodigestion is very active, and this allows tumor cells to obtain energy, prevent the accumulation of toxic components, and thus divide and proliferate. When RAB7 is reduced, cells use endosomes to recycle metastatic proteins, favoring their dispersal throughout the body.

Defining "the key to the fate of the tumor cell," as Soengas explained, is just one of many new aspects of melanoma uncovered by this study, published in Cancer Cell (2014; doi:10.1016/j.ccr.2014.04.030).

"Finding which mechanisms determine why melanoma is so aggressive is very complex because more than 80,000 mutations have been described for this tumor," said first author Direna-Alonso Curbelo, PhD, of CNIO.

Relevant to melanoma prognosis, the authors used tumor biopsies to show that the amount of RAB7 in a cutaneous tumor defines the risk of metastasis. "This study opens avenues for the potential use of proteins that control vesicles and regulate autophagy as novel markers of patient survival," said Soengas.

Furthermore, these results help to understand the mechanism of action of a compound that, as the group discovered in 2009, is lethal in melanoma cells as well as in other tumor cells. This RNA-based nanoparticle compound kills the cells by acting on the formation of vesicles.

"We knew how our nanoparticles act inside tumor cells, but not how they selectively incorporate inside the cells,” said Soengas. The size of these molecules requires cells to form endosomes in order to be able to trap the compound. This study demonstrates that this endosome formation (via RAB7) is very active in tumor cells but not in normal cells. Normal cells, therefore, do not incorporate RNA nanoparticles, reducing the risk of toxic effects.

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