New insights into melanoma brain metastases

Brain metastases are one of the most common causes of death from cancer and occur very frequently in patients with advanced melanoma. Although newer immunotherapies are effective in some patients with melanoma brain metastases, little is known about the reasons for melanoma spread to the brain and the lower response rates to many treatments.

Columbia researchers have now completed one of the most comprehensive studies of cells within melanoma brain metastases, uncovering details that could fuel the development of a new generation of therapies.

“Brain metastases are extremely common in melanoma patients, but we only had a rudimentary understanding of the underlying biology,” says study leader Benjamin Izar, MD, PhD, an assistant professor of medicine at the Vagelos College of Physicians and Surgeons of Columbia University. “Our study gives us new insights into the genomics, immunology, and spatial organization of these tumors and serves as a foundation for new discoveries and therapeutic explorations. »

The results have been published online at cells.

Innovative methods enable deeper analysis

To begin to understand why brain metastases from melanoma elude current treatments, Izar and his team needed to invent new techniques for performing single-cell genetic analysis of frozen brain samples.

“Such studies are usually done on fresh brain samples, which are rare and severely limit the number of tumors that can be analyzed. Instead, we have many frozen melanoma samples in our tissue bank,” says Izar.

“This innovation also allowed us to analyze tissue from patients who had not been treated, allowing us to see the biology of the tumor and its microenvironment before they were altered by therapy. »

Revealed therapeutic targets

Using metastatic tumors from several dozen melanoma patients, Izar and colleagues analyzed the genes expressed in more than 100,000 individual cells.

The analysis revealed that melanoma brain metastases are chromosomally more unstable than melanoma metastases elsewhere in the body.

“Chromosomal instability is the perpetual gain and loss of large chromosome fragments; this process triggers signaling pathways that make cells more likely to spread and more capable of suppressing the body’s immune response,” says Johannes C. Melms, MD, a postdoctoral molecular researcher in the Izar lab and one of the first study authors.

These pathways could be important therapeutic targets. “Several experimental drugs that reduce chromosomal instability will soon be tested in humans,” says Melms. “Now we have a rationale to test these drugs in patients with melanoma metastases to the brain. »

Hide from the immune system

The researchers also discovered two other features of melanoma brain metastases that may help hide cells from the patient’s immune system. Researchers have found that metastases alter immune cells, specifically macrophages and T cells, in the tumor microenvironment in ways that promote cancer growth. And they found that cells enter a neuron-like state within the brain.

“It is possible that these changes help tumor cells adapt and survive in their new environment while avoiding subsequent immune responses,” says Jana Biermann, PhD, a postdoctoral researcher in informatics in the Izar lab and one of the first authors of the study.

First spatial analysis

Finally, the researchers were able to perform the first spatial analysis of melanoma brain metastases, analyzing and collating scans of multiple tumor slices in the same way that a CT scanner creates three-dimensional images.

“It turns out that there is great geographic variability from tumor to tumor and even within the same tumor, in terms of metabolic and immune pathways,” says Izar.

“We are just beginning to understand how to think about spatial variability, but it is clear that this will be essential to increase the chances of complete tumor responses to new therapies. »

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