CNIO researchers explore new ways of attacking melanoma, an increasingly frequent cancer in which prevention is crucial

• By investigating the origin and evolution of melanoma, several groups at the Spanish National Cancer Research Center (CNIO), who are international leaders in the field, have come up with promising strategies.
• The Melanoma Group, led by Marisol Soengas, seeks to inhibit proteins that help the tumor evade the body's natural defenses.
• The Microenvironment and Metastasis Group, led by Héctor Peinado, aims to prevent the formation of the 'nest' that allows the tumor to spread to other organs.

In this video, the melanoma cells (in green) on the left have proteins that trick our defense system and get it to work in favor of the cancer, promoting its development instead of attacking it. This is why melanoma cells survive despite being surrounded by defensive cells (in red), the cytotoxic lymphocytes.

In contrast, the melanoma cells on the right do not have their anti-defense proteins active, and so the lymphocytes do attack the tumor cells, which eventually disappear from the image.

The Melanoma Group at the Spanish National Cancer Research Center (CNIO) discovered these ‘anti-defense’ proteins in melanoma cells a few years ago, and are now exploring strategies to block them. Meanwhile, the CNIO’s Microenvironment and Metastasis Group is working on what could become one of the first treatments against melanoma metastasis in its early stages.

Prevention of the most invasive skin cancer

Melanoma is the most aggressive skin cancer. According to the Spanish Society of Medical Oncology (SEOM), more than 7,000 new cases of skin melanoma are diagnosed in Spain every year. The incidence is increasing.

Its main risk factor is exposure to the sun. Ultraviolet (UV) light damages the DNA of exposed cells, which generates mutations that can turn the cells into tumor cells.

Skin cancer is therefore a type of tumor for which prevention is particularly effective. It is important to avoid prolonged exposure to the sun and to use high protection creams. It is also important to be alert to new moles and to changes in existing ones (size, color, shape, bleeding). Early diagnosis multiplies the healing chances.

Seeing metastases before they happen

To get to cure melanome, it is necessary to understand first the origin and evolution of this tumor and its ability to metastasize (invade other organs). At the CNIO, the Melanoma Group, led by Marisol Soengas, has managed to visualize how melanoma starts and progresses from very early stages.

One of the experimental models they have developed is the “MetAlert” system, to visualize how melanoma cells prepare dissemination routes before metastasis occurs. This allows to identify new genes and new therapies that “turn the tumor on or off,” Soengas explains.

“With MetAlert we identified a new pro-metastatic protein, MIDKINE, which also has immunosuppressive effects,” Soengas points out.“We are now developing MIDKINE inhibitors through several collaborations at the CNIO: with the Monoclonal Antibodies Unit, led by Giovanna Roncador, and the Experimental Therapeutics Program, headed by Joaquín Pastor.

Soengas’ group is also interested in other proteins that act like “Jeckyll and Hyde”, perverting the body’s defenses in a way that prompt them to, instead of attacking the tumor, promote its development. In the video at the beginning of this note –obtained with fluorescence microscopy– melanoma cells express one of these proteins, STAU1.

Preventing metastasis from ‘nesting’

Meanwhile, the CNIO’s Microenvironment and Metastasis Group, led by Héctor Peinado, has discovered what could become one of the first treatments against melanoma metastasis in its early stages.

The researchers discovered a molecule that prepares the ‘nest’ in the organ in which the melanoma will reproduce, and found that blocking it reduces metastasis in animal models. They have found a non-toxic compound that prevents the action of this molecule, called NGFR.

They are now preparing “a publication presenting the results of its use in combination with immunotherapy to treat melanoma,” says Héctor Peinado.

Further information about the video and images:

Video: On the left melanoma cells (in green) can be seen surviving in the presence of cytotoxic lymphocytes (red), when they express one of these immunosuppressive proteins. If this protein is inactivated or lost, the lymphocytes attack the tumor cells and so the latter end up disappearing from the image. / Melanoma Group. CNIO.

Image 1: Analysis of NGFR expression (violet) in metastatic melanoma tumor cells in the lymph node (brown). Credit: CNIO Microenvironment and Metastasis Group.

Image 2: Tumors, such as melanoma, release nanovesicles called exosomes (gray) that travel and lodge in the lymph nodes. There they corrupt the behavior of lymph cells. The lymphatic vessels (green) branch out more than usual and allow the tumor cells to survive and migrate to other organs. This process can be seen here in the sentinel lymph node (where metastasis begins to occur) whose structure is shown in red. Credit: CNIO Microenvironment and Metastasis Group.

Image 3: Structure of a lymph node whose endothelial cells (green) are capturing the nanovesicles called exosomes (red) that have moved to the node from a tumor. Credit: CNIO Microenvironment and Metastasis Group.