Blocking melanoma's 'escape route'

In order to escape treatment, melanoma sometimes reverts to a previous stage of cell differentiation. New research investigates this process more closely and finds a potential way to block this skin cancer's escape route.

Although rare, melanoma is a very aggressive form of skin cancer that can prove fatal.

Of all skin cancers, melanoma has the highest mortality rate and the highest potential to spread.

It is particularly difficult to treat when it mutates and can therefore become treatment-resistant.

Though the latest advances in immunotherapy have drastically improved survival rates and outcomes for people with this mutant form of melanoma, there are still those who do not respond as well to these treatments, or whose cancer returns.

Now, researchers at the University of California, Los Angeles (UCLA) — led by Thomas Graeber, a professor of molecular and medical pharmacology — set out to investigate in more detail how this cancer changes in order to evade treatment.

The scientists examined the process of dedifferentiation — that is, the process in which melanoma cells regress to an earlier stage of embryonic development — and found that, depending on the stage that they're in, melanomas can be broken down into four different subtypes.

Of these subtypes, the researchers found, some are vulnerable to a type of cell death.

Importantly, this type of cell death can be induced with certain drugs, and, as the new research reveals, using these drugs in combination with existing anticancer therapies could block melanoma's escape.

The findings were published in the journal Cancer Cell.

Finding four subtypes of melanoma

Melanoma emerges from the skin's pigment-producing cells, or melanocytes. Prof. Graeber and colleagues carried out a gene expression analysis of melanoma cells, and, using stem cell technology, they also created melanocytes.

Then, the researchers compared the genetic expression of melanoma cells — as obtained from public genetic databases — with that of melanocytes.

The analysis revealed that melanoma cells can be divided into four subgroups, according to the genes that are activated and deactivated in each differentiation stage.

"This refined characterization improves our understanding of the progressive changes that occur in melanoma cells during dedifferentiation, which can help develop better strategies to target this form of therapy resistance," says first study author Jennifer Tsoi, a UCLA researcher.

Ferroptosis may block melanoma's escape

Prof. Graeber and team also analyzed the various levels of drug sensitivity that corresponded with differentiation stages. The scientists searched for drugs that could be used either separately or in combination to target the different stages of melanoma dedifferentiation.

The researchers discovered "a heightened sensitivity to ferroptosis induction with the degree of differentiation." Ferroptosis is a form of cell death that can be triggered and is different from the naturally occurring apoptosis — that is, the normal cell death that takes place as a result of an organism's evolution.

Finding this vulnerability to ferroptosis has important therapeutic implications, explain the authors, as "ferroptosis-inducing drugs" are a good "therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies."

Immune therapies are more successful when used against differentiated cells than non-differentiated ones, explain the authors.

"Furthermore, these standard-of-care therapies can induce dedifferentiation, and thus in a co-treatment setting, ferroptosis induction can potentially block melanoma cells attempting to take this escape route."

Prof. Thomas Graeber