Brain metastases are one of the most common causes of cancer-related death and occur very frequently in patients with advanced melanoma. Although new immunotherapies are effective in some patients with melanoma brain metastases, little is known regarding the reasons for the spread of melanoma to the brain and the lower response rates to many treatments.
Columbia researchers have now completed one of the most comprehensive studies of the cells inside melanoma brain metastases, uncovering details that might spur 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, assistant professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons. “Our study gives us new insights into the genomics, immunology and spatial organization of these tumors and serves as a basis for new discoveries and therapeutic explorations. »
The results have been published online in Cells.
Innovative methods allow for deeper analysis
To begin to understand why melanoma brain metastases elude current treatments, Izar and his team needed to invent new techniques to perform single-cell genetic analyzes of frozen brain samples.
“Such studies are typically performed on fresh brain samples, which are rare, severely limiting the number of tumors that can be analyzed. In contrast, 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. »
Therapeutic targets unveiled
With metastatic tumors from several dozen melanoma patients, Izar and his colleagues analyzed the genes expressed in more than 100,000 individual cells.
The analysis revealed that melanoma brain metastases are more chromosomally unstable than melanoma metastases in other parts of the body.
“Chromosomal instability is the perpetual gain and loss of large chromosomal fragments; this process triggers signaling pathways that make cells more likely to spread and better able to suppress the body’s immune response,” says Johannes C. Melms, MD, postdoctoral molecular researcher in the Izar lab and one of first authors of the study.
These pathways might be important therapeutic targets. “Several experimental drugs that reduce chromosomal instability will soon be tested in humans,” says Melms. “We now have a rationale for evaluating these drugs in patients with melanoma metastases in 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. The researchers found that metastases alter immune cells, specifically macrophages and T cells, in the tumor microenvironment in ways that promote cancer growth. And they discovered that cells go into a neuronal-like state inside the brain.
“It’s possible that these changes help tumor cells adapt and survive in their new environment while avoiding ensuing immune responses,” says Jana Biermann, PhD, postdoctoral computing researcher at the Izar lab and the 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 the 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 a given tumor, in terms of metabolic and immune pathways,” says Izar.
“We are just beginning to understand how to think regarding spatial variability, but it is clear that this will be essential to increase the chances of complete tumor responses to new therapies. »