The discovery does not bring a new therapy, but it helps us better understand how melanoma cells behave and which molecular mechanisms could be investigated in the future development of therapeutic approaches.

“Melanoma is the most dangerous form of skin cancer precisely because it can spread to other parts of the body. Although there are currently no approved drugs that target adhesion proteins in the treatment of melanoma and other tumours, a large number of studies are addressing this topic. This research does not represent a new therapy, but it provides important knowledge about the relationship between adhesions in melanoma cells. More basic research into the role of adhesion proteins may contribute to the faster and more successful development of drugs targeting these molecules in the future,” explains Dr. Nikolina Stojanović from the Laboratory for Cell Biology and Signalling at IRB, who shares corresponding and first authorship on both papers.

How do melanoma cells start moving?

The tissues in our body are made up of a large number of cells that are not static. They constantly form and break connections with other cells and with the environment in which they are located. These sites of connection, which allow cells to “hold on” to their surroundings, are called adhesions. Not all adhesions are the same, different types of adhesions have different roles, and their formation and disappearance are crucial for cell movement. In cancer cells, including melanoma cells, this movement can enable the disease to spread to other parts of the body, resulting in metastasis.

To investigate these processes in greater detail, the research team focused on the protein KANK2, one of the molecules that helps the cell organise its internal structures and adjust the way it connects with its surroundings. Such proteins are important because they influence cell behaviour, including the cell’s ability to move.
“In the study described in the paper KANK2 at focal adhesions regulates their maintenance and dynamics, while at fibrillar adhesions it influences cell migration via microtubule-dependent mechanism, we showed that the KANK2 protein in melanoma cells is found in two different types of adhesions, the sites through which the cell attaches to its surroundings. One type is located at the edge of the cell, while the other is closer to its centre. Although this is the same protein, its role in these adhesions is not the same. When scientists reduced the amount of KANK2 at the edges of the cell, where one type of adhesion is located, the cells moved more slowly. However, when they reduced it in the central parts of the cell, where another type of adhesion is found, the cells became more mobile, as if a brake that had previously held them back had been removed,” explains Dr. Andreja Ambriović Ristov, head of the Laboratory for Cell Biology and Signalling and one of the two corresponding authors of the papers.

This discovery shows that, inside a cell, it is not only important which protein is present, but also where it is located and which other molecules it is connected to. In other words, the same protein can perform different roles, depending on its “workplace” within the cell. This part of the research attracted the attention of the scientific community, and the paper was also featured on preLights, a platform run by The Company of Biologists, where scientists highlight and comment on particularly interesting biological research.

One protein, three roles in melanoma cells

In the next step, the researchers sought to better understand the composition of a third type of adhesion, how these adhesions behave in melanoma cells, and the roles played by the proteins KANK2 and talin2. In the second paper, Regulation of reticular adhesions by KANK2 and talin2 in two melanoma cell lines, published only two months after the first paper in the same journal, Cell Communication and Signaling, the research team showed that the KANK2 protein in melanoma cells is also found in this third type of adhesion, through which the cell attaches to its surroundings. These adhesions were discovered relatively recently and have not yet been sufficiently explored. So far, it is known that they play an important role during cell division, and they are particularly interesting because, unlike other adhesions, they are not directly connected to the internal network of structures that gives the cell its shape and enables it to move.

The results further confirm the conclusion of the first paper, namely that a single protein in a cell can have multiple roles that change depending on its location and interactions within the cell.

“Our results show that the role of a protein does not depend only on its presence, but also on where it is located in the cell and which structures it communicates with. This is precisely why protein function needs to be studied at multiple levels, especially when it comes to proteins that could become targets for cancer treatment. In addition to mutations and messenger RNA expression, it is also important to analyse the location of proteins within the cell, which is something we paid particular attention to in both of our papers,” explains Dr. Andreja Ambriović Ristov.

The researchers also showed that different types of cell adhesions are interconnected and in constant communication, meaning that changes in one type can trigger changes in others.

“It is particularly interesting that different melanoma cells, obtained from different patients, can have different types of adhesions. Because several types of adhesions within a single cell are interconnected, it is not easy to predict how melanoma cells will behave after targeting individual adhesion proteins. In addition, our results show that in different melanoma cells, KANK2 does not always bind to the same proteins. We still do not know how to explain why this happens. This is why it is important to continue basic research into adhesions, so that we can clarify all the roles of adhesion proteins in the cell and correctly select target molecules for reducing melanoma metastasis,” emphasises Dr. Nikolina Stojanović.

A step towards a better understanding of cancer spread

“The next step will be to test whether the same mechanism also exists in primary melanoma cells isolated from patients, in other words, in cells that more closely resemble real melanomas in the body,” concludes Dr. Marija Lončarić, a postdoctoral researcher in the Laboratory for Cell Biology and Signalling, who participated in both studies and shares first authorship on one of the papers. She is working on primary melanoma cells to determine whether they behave in the same way as established cell cultures, and in the future she plans to carry out part of the experiments on 3D melanoma models.

In addition to the corresponding authors Dr. Andreja Ambriović Ristov and Dr. Nikolina Stojanović, the authors who share first authorship are postdoctoral researchers Dr. Marija Lončarić and Dr. Anja Rac. Other contributors include IRB research associates Dr. Ana Tadijan, Dr. Mladen Paradžik and Dr. Dalibor Hršak, two graduate students, Marta Acman and Mirna Rešetar, collaborator Dr. Jonathan D. Humphries from Manchester Metropolitan University, and Prof. Dr. Martin J. Humphries and Dr. Mahak Fatima from the University of Manchester. The research was supported by the Croatian Science Foundation through project IP-2019-04-1577, led by Dr. Andreja Ambriović Ristov, Cancer Research UK, led by Prof. Dr. Martin J. Humphries, and the Academy of Medical Sciences Springboard Award, led by Dr. Jonathan D. Humphries.

References to the papers and the preLights commentary

• Stojanović N, Rac A, Lončarić M, Tadijan A, Paradžik M, Acman M, Humphries JD, Humphries MJ, Ambriović-Ristov A. KANK2 at focal adhesions regulates their maintenance and dynamics, while at fibrillar adhesions it influences cell migration via microtubule-dependent mechanism. Cell Commun Signal. 2026 Mar 3;24(1):224.
• Rac A, Lončarić M, Stojanović N, Fatima M, Rešetar M, Hršak D, Humphries JD, Humphries MJ, Ambriović-Ristov A. Regulation of reticular adhesions by KANK2 and talin2 in two melanoma cell lines. Cell Commun Signal. 2026.
• KANK2 at focal adhesion regulates their maintenance and dynamics, while at fibrillar adhesions it influences cell migration via microtubule-dependent mechanism