About 150,000 new cases of melanoma are diagnosed each year in Europe, a number that is expected to increase due to climate change and other factors. Despite its high incidence, many aspects of the process that causes its appearance and spread are still unknown.

A study by the Biomedical Research in Melanoma group at Vall d'Hebron Research Institute (VHIR), with the collaboration of the Dermatology Service of Vall d'Hebron University Hospital and the Clinical Oncology programme of Vall d'Hebron Institute of Oncology (VHIO), has discovered a mechanism that contributes to the transformation of melanocytes, the melanin-producing cells, which could explain the appearance of melanomas without a clear primary origin, i.e. without the existence of an associated nevus, whether a freckle or a spot.

This mechanism is linked to exposure to ultraviolet radiation, the main environmental factor linked to the appearance of this skin tumour.

Additionally, the research, published in the scientific journal Oncogene, has identified UPP1, a molecule involved in this process, as a promising therapeutic target.

The role of BRAFv600E, one of the great enigmas of melanoma

One of the great enigmas of melanoma research is why some melanocyte growth processes produce benign nevus like freckles, while others develop into malignant melanomas. There is also a small percentage, between 25 and 33%, that start as benign nevus and, over time, progress to melanoma.

Current research has focused on the role of the BRAFv600E mutation in this process and in whether or not a melanoma develops. It is known that this mutation is present in 80% of nevus, and that during the formation of a freckle, this mutation initially stimulates the growth of melanocytes, but at a later stage slows down their proliferation. However, it is also present in 50-60% of diagnosed malignant melanomas, which means that in some cases the mutation activates the first phase, the growth phase, but not the second phase, in which tumour suppressor mechanisms develop. And until this research, the circumstances leading to the different behaviour of this oncogene were unknown.

Dr Ángel Recio, head of the Biomedical Research in Melanoma group at VHIR and director of the study, explains that the “fact that exposure of newborns to UV radiation of sufficient intensity to cause a skin reaction”, such as erythema (reddening of the skin) or blistering, "causes a significant increase in the probability of having melanoma in the future, was well-known, but it was not understood how it happened. Now, this study has revealed that if this exposure occurs simultaneously with the activation of BRAFv600E, it triggers a reprogramming in gene expression that allows the uncontrolled proliferation of cancer cells".

To explain and isolate the exact genetic and molecular changes in gene reprogramming caused by UV radiation that allow the suppressive mechanisms of the BRAFv600E oncogene to be overcome, the research team looked for a new model that, without being directly exposed to UV rays, would obtain similar results. This is how they were able to identify that the loss of the LKB1 kinase is the key factor in this process.

A potential new therapeutic target
 

Based on these findings, a comparative analysis of gene expression before and after activation of the identified mechanisms was carried out. The study found the molecule UPP1 as a potential therapeutic target. Blocking this molecule could hinder tumour cell viability and slow melanoma progression. Although further studies are needed to confirm its efficacy in humans, this breakthrough opens a new avenue in the fight against melanoma.

According to Dr. Recio, ‘regardless of the evolution of UPP1 research, understanding the molecular processes that facilitate the appearance of melanoma is a fundamental step towards developing medical and public health strategies to help reduce the incidence of this disease,’ which continues to increase.
 

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