Melanoma is one of the types of cancer that poses the greatest challenge to researchers because it manifests itself in many ways, it contains a large number of mutations and displays high metastatic capacity. To date, clinicians mostly base their diagnosis on physical measurements, with a tumour depth of two millimetres and above implying a poor prognosis. Now, a study from researchers at the Spanish National Cancer Research Centre (CNIO) shows that melanoma patients with partial loss of a protein called ATG5 have a worse prognosis due to a link with autophagy, a process which enables the orderly degradation and recycling of cellular components. The team state that their findings have important translational implications in drug design, as partial blockade of autophagy genes may worsen the malignancy of metastatic melanomas. The study is published in the journal Autophagy.
Previous studies show that the ATG5 protein is essential for autophagy; a process that is usually beneficial for cells to self-degrade their own components when they are no longer useful. However, autophagy can also be a double-edged sword for tumour cells as any excess self-cannibalism can be harmful. Therefore, cells have to be very careful about how they regulate and to what levels they trigger the autophagy process to survive. The factors that act as keys or switches of autophagy are still unknown today. The current study investigates how important autophagy is for melanomas, and the mechanisms that underlie dual pro- and anti-tumourigenic functions of this process.
The current study analysed 20 autophagy genes in more than 25 different types of cancer using databases that contained information of almost five thousand patients. Results show a huge variability between the different types of tumours, with only alterations in the ATG5 gene providing diagnostic value in melanoma. Data findings show that melanoma cells limit ATG5 levels by selectively losing one of the copies of this gene; a process that does not occur in relation to other autophagy factors.
To study the role of ATG5 in vivo, the lab created genetically modified mice where they induced a selective loss of one of the copies of the ATG5 gene. Results show that when one copy of this gene is lost the tumours have a poor prognosis, with metastasis and death, which was also observed in patients. Data findings in these animal models show that when tumours lose only one copy of ATG5, they become more aggressive and metastatic, and respond less to targeted therapies for melanoma.
The team surmise that their findings provide a switch that regulates autophagy and favours metastasis. They believe that this information will greatly enhance capacity to predict prognosis. For the future, the researchers state that this molecular marker commonly found in cutaneous melanoma will also open up other areas of research on less common and less-studied melanomas, such as ocular or mucous melanomas. They conclude that the chromosome where ATG5 resides is lost in ocular melanoma, hypothesizing that it is worth exploring its role in this type of melanoma.