“Self-Eating” Cells May Help Prevent Melanoma Progression

A new study in early-stage melanoma patients shows that the process of “self-eating” or autophagy can keep the cancer in check. Researchers at the University of Bern in Switzerland show that the cell process can help control tumor growth of melanoma and identify the autophagy protein 5 (ATG5) as a tumor suppressor. The results of the study, published in Science Translational Medicine, suggest early-stage melanoma patients may have a better prognosis if their tumors have a high expression level of ATG5.

Autophagy is a process that clears out cellular garbage and debris from living cells, including DNA, proteins, and organelles. This cellular garbage is shuttled to specific cellular compartments and degraded by lysosomal enzymes. While the primary role for this process is survival during stress, autophagy is also linked to aging and immunity.

While high autophagy has been thought to promote survival of cancer cells (since cancer cells are under stress from genomic instability and treatment exposure, for example), the new study suggests that a low level of autophagy promotes early tumorigenesis in melanoma cells. “This surprised us,” said lead author Hans-Uwe Simon, professor of pharmacology and director of the department of pharmacology at the University of Bern.

Simon and colleagues show that while high autophagy can stave off development of advanced melanoma, low autophagy levels contribute to cancer development.

The researchers found that mRNA levels of ATG5 are low in primary melanoma lesions compared with benign melanocytic nevi. In an analysis of 194 melanoma samples and 150 nevus samples from patients, ATG5 was significantly less expressed in the melanoma samples (P < .001). Using a second cohort of 158 melanoma patients, the researchers found those melanomas with higher ATG5 expression had a significantly better progression-free survival (P = .03). ATG5 levels in the melanoma samples correlated with autophagy activity as measured by LC3 levels. LC3 is a marker for autophagy.

Similar results were observed for seven melanoma cell lines examined.

While mutations in the ATG5 gene were not identified, the researchers found the promoter of the gene could be hypermethylated, which could reduce expression of ATG5.

In an in vitro model of melanoma tumorigenesis, reducing autophagy can provide a growth advantage. Increasing expression of ATG5 increased autophagy, reduced growth of two melanoma cell lines, and boosted senescence.

This study provides a model for the formation of a melanoma: once a melanocyte undergoes transformation, formation of a tumor can be prevented by apoptosis or senescence, with autophagy contributing to tumorigenesis prevention through cellular senescence.

“Assessment of the ATG5 status can help in the differential diagnosis between benign nevus and primary melanoma, appears to be of prognostic relevance, and may provide therapeutic options for the management of patients with melanoma,” stated the authors.

Still, further studies are needed. Samples from a larger cohort of melanoma patients need to be analyzed to confirm these results.

The researchers are also investigating the role of autophagy in other tumor types. “We are in the process of analyzing ATG5 expression in other types of cancers and also other autophagy-regulating proteins,” said Simon. Whether autophagy and ATG5 specifically are downregulated in other cancers is not known.