One of the most prevalent causes of cancer-related mortality is brain metastasis, which usually affects people with advanced melanoma. Although some patients with melanoma brain metastases respond well to novel immunotherapies, little is understood about the causes of melanoma brain metastases and the poor response rates to numerous treatments.
One of the most thorough investigations of the cells inside melanoma brain metastases has now been completed by Columbia researchers, who have uncovered information that may help create a new wave of treatments.
According to research leader Benjamin Izar, MD, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, "brain metastases are quite prevalent in individuals with melanoma, but we have only had a basic grasp of the underlying biology." Our research provides fresh understanding of the immunology, genetics, and spatial organization of these malignancies and lays the groundwork for future research and therapeutic investigation.
Cell published the findings online.
New techniques enable deeper investigation.
Izar and his team had to develop new methods for single-cell genetic analyses of frozen brain samples in order to start understanding why melanoma brain metastases evade current therapies.
"The number of tumors that may be studied is severely constrained by the fact that such studies are often conducted on fresh brain samples, which are in limited supply. In contrast, our tissue bank has a large number of frozen melanoma samples "Izar claims.
With the help of this innovation, we were also able to examine tissues from patients who had not yet received treatment, allowing us to understand the biology of the tumor and its microenvironment before treatment could change them.
Discovered therapeutic targets
Izar and his associates examined the expression of more than 100,000 distinct genes in metastatic tumors from several dozen melanoma patients.
According to the data, melanoma metastases in the brain are more chromosomally unstable than those in other areas of the body.
According to Johannes C. Melms, MD, a molecular postdoctoral fellow in the Izar lab and one of the study's first authors, "Chromosomal instability is the continual 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."
Potentially significant therapeutic targets are these pathways. In the near future, Melms says, "a number of investigational medications that decrease chromosomal instability will be evaluated in people." We now have a justification for testing these medications on those who have brain metastases from melanoma.
avoidance of the immune system
Two other features of melanoma brain metastases that the researchers discovered may aid in shielding the cancer cells from the patient's immune system. The scientists discovered that the metastases change the macrophages and T cells in the tumor microenvironment in a way that encourages the progression of cancer. Additionally, they discovered that within the brain, the cells take on a neuronal state.
According to Jana Biermann, PhD, a computational postdoctoral scholar in the Izar lab and one of the study's lead authors, "It's plausible that these alterations allow tumor cells adapt and survive in their new habitat while escaping subsequent immune responses."
spatial analysis is first.
Finally, by combining assessments of different tumor slices in a manner similar to how a CT scanner produces three-dimensional pictures, the researchers were able to undertake the first spatial study of melanoma brain metastases.
In terms of metabolic and immunological pathways, "it turns out there's quite a bit of regional heterogeneity from one tumor to the next and even inside a particular tumor," claims Izar.
Although we are only beginning to comprehend how to conceptualize spatial variability, it is obvious that this will be crucial to improving the likelihood that innovative medicines can completely eradicate tumors.
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Materials provided by Columbia University Irving Medical Center. Note: Content may be edited for style and length.
