a mutation would facilitate the formation of metastases ⋅ Inserm, From science to health

Within a melanoma, some cells carry a genetic mutation that affects their ability to adhere. When they lack a growth factor, they would have an easier time disseminating in the body. The in-depth analysis of this mechanism could make it possible to identify therapeutic targets in order to prevent the phenomenon.

A cancer is said to be metastatic when a new tumor forms at a distance from the initial tumour. To date, the mechanisms by which cancer cells spread in the body and form these metastases are not all well described. This is particularly the case for melanoma, an aggressive skin cancer, structured very differently from breast, lung or colon cancers, which are otherwise better understood.

By exploring the biology of melanoma, Julien Ablain’s team, in collaboration with Leonard Zon’s group at Boston Children’s Hospital (United States), discovered a very particular mechanism, which combines both a genetic factor and a of cellular stress. ” We first observed that the gene that codes for a cell adhesion molecule, nectin-1, is more often lost in the cells of melanoma metastases than in those of melanomas themselves “, explains the researcher. Nectin-1 protein participates in the formation of junctions between cells, it helps the tissue to maintain its integrity. Consequently, the loss of the gene which encodes this protein can promote the dissemination of tumor cells: the cells which no longer carry it will more easily migrate out of the primary tumor than those which still express it.

However, even when the gene is lost, the formation of metastases is not systematic. Other phenomena must intervene to lead to this cell migration. The researchers discovered the role of cellular stress caused by a deficiency in IGF‑1. ” This cell growth factor circulates in the body where it promotes the proliferation and survival of certain cells, in particular those of tumor cells. If this factor is lacking, the tumor cells try to adapt by forming junctions between them thanks to nectin-1. But when the gene coding for nectin-1 has been lost, they are unable to do so and can disseminate more easily. »

A necessary and sufficient path?

The researcher now wants to understand by which specific mechanisms IGF-1 and nectin-1 interact. For this, he wishes to continue this work, carried out on human cell cultures and in zebrafish, a reliable animal model for the study of melanoma. ” Understanding the reciprocal relationships between these two actors could help identify potential therapeutic targets and tackle the mechanisms of dissemination of melanoma cells.he explains. Since IGF-1 promotes cell proliferation, it is difficult to imagine increasing its concentration at the tumor level. But if we finely understand the entire cellular response to IGF-1 deficiency, we may be able to hijack it in a way that pushes tumor cells into a dead end that would promote their death.. To do this, Julien Ablain wants to identify all of the cellular signals activated by low availability of the growth factor. ” We want to know if the interaction between nectin-1 and IGF-1 is sufficient to cause the dissemination of tumor cells, or if other mechanisms are involved simultaneously. Furthermore, it is important to keep in mind that melanomas are heterogeneous “, he insists. Within the same tumor, the cells can in fact present none, one or two copies of the gene for nectin-1. On the other hand, depending on their location within the tumor mass, not all of them are exposed to the same concentrations of circulating IGF-1. ” We must also expect heterogeneity in the behavior of melanomas from one patient to another. Nevertheless, one may wonder whether the loss of the nectin-1 gene could constitute a prognostic factor for the development of melanoma. Also, additional studies could make it possible to assess whether the search for this genetic anomaly during the initial diagnostic assessment of the disease would be useful in guiding its management.

Julien Ablain is responsible for the team Adhesion and signaling in metastatic melanoma