New Insights into Melanoma Brain Metastases
Brain metastasis is one of the most common causes of cancer-related deaths and occurs very frequently in patients with advanced melanoma. Although new immunotherapies are effective in some patients with melanoma brain metastases, little is known about the reasons for melanoma’s spread to the brain and the lower response rates to many therapies.
Columbia researchers have now completed one of the most comprehensive studies of the cells inside melanoma brain metastases, uncovering details that could spur the development of a new generation of therapies.
“Brain metastases are extremely common in patients with melanoma, but we have 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 foundation for further discovery and therapeutic exploration.”
The findings were published online in Cell.
Innovative methods allow for deeper analysis
To begin understanding why melanoma brain metastases evade current treatments, Izar and his team needed to invent new techniques for performing single-cell genetic analyses of frozen brain samples.
“Such studies are typically performed on fresh brain samples, which are in short supply, drastically limiting the number of tumors that can be analyzed. In contrast, we have many frozen melanoma samples in our tissue bank,” Izar says.
“This innovation also allowed us to analyze tissues from patients who had not been treated, letting us see the biology of the tumor and its microenvironment before they're altered by therapy."
Therapeutic targets revealed
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, a molecular postdoctoral fellow in the Izar lab and one of the study’s first authors.
These pathways could be important therapeutic targets. “Several experimental drugs that reduce chromosomal instability are going to be tested in humans soon,” Melms says. “We now have a rationale to evaluate these drugs in patients with melanoma metastases in the brain.”
Hiding from immune system
The researchers also uncovered two other characteristics of melanoma brain metastases that may help to hide the cells from the patient’s immune system. The researchers found that the metastases alter immune cells, specifically macrophages and T cells, in the tumor microenvironment in a way that promotes cancer growth. And they found that the cells adopt 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, a computational postdoctoral fellow in the Izar lab and one of the study’s first authors.
First spatial analysis
Finally, the researchers were able to perform the first spatial analysis of melanoma brain metastases, by analyzing and piecing together analyses of multiple slices of the tumors much the way a CT scanner creates three-dimensional images.
“It turns out there’s quite a bit of geographic variability from one tumor to the next and even within a given tumor, in terms of metabolic and immune pathways,” says Izar.
“We are just beginning to understand how to think of spatial variability, but it’s clear that this will be key to increasing chances for complete tumor responses to novel therapies.”
The study is titled, “Dissecting the treatment-naïve ecosystem of human melanoma brain metastasis.”
All authors (Columbia unless noted): Jana Biermann, Johannes C. Melms, Amit Dipak Amin, Yiping Wang, Lindsay A. Caprio, Alcida Karz (New York University), Somnath Tagore, Irving Barrera (Broad Institute), Miguel A. Ibarra-Arellano (Heidelberg University), Massimo Andreatta (Heidelberg University and University of Lausanne), Benjamin T. Fullerton, Kristjan H. Gretarsson, Varun Sahu, Vaibhav S. Mangipudy, Trang T.T. Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D. Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H. Walsh, Shivem B. Shah, Daniel H. Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann (Heidelberg University), Margot Chazotte (Heidelberg University), Simon Berhe, Adrienne M. Luoma (Dana-Farber Cancer Center), Joseph Driver (Harvard), Matthew Ingham, Shaheer A. Khan, Suthee Rapisuwon (Georgetown University), Craig L. Slingluff Jr. (University of Virginia), Thomas Eigentler (Eberhard Karls University, Freie Universität Berlin, and Humboldt-Universität zu Berlin), Martin Röcken (Eberhard Karls University), Richard Carvajal, Michael B. Atkins (MD Anderson Cancer Center), Michael A. Davies (Memorial Sloan Kettering Cancer Center), Albert Agustinus (Memorial Sloan Kettering Cancer Center and Cornell University), Samuel F. Bakhoum (Memorial Sloan Kettering Cancer Center), Elham Azizi, Markus Siegelin, Chao Lu, Santiago J. Carmona (University of Lausanne and Swiss Institute of Bioinformatics), Hanina Hibshoosh, Antoni Ribas (University of California, Los Angeles), Peter Canoll, Jeffrey N. Bruce, Wenya Linda Bi (Harvard and Dana-Farber Cancer Institute), Praveen Agrawal (Albert Einstein College of Medicine), Denis Schapiro (Heidelberg University), Eva Hernando (New York University), Evan Z. Macosko (Broad Institute and Massachusetts General Hospital), Fei Chen (Broad Institute and Harvard University), Gary K. Schwartz, and Benjamin Izar.
The research was supported by the National Institute of Health (grants K08CA222663, R37CA258829, U54CA225088, R21CA263381, T32GM007367, P50CA221703, U54CA224070, P30CA051008, and P30CA013696); an American Cancer Society Research Scholar Grant; a Burroughs Wellcome Fund Career Award for Medical Scientists; a Velocity Fellows Award; the Louis V. Gerstner Jr. Scholars Program; a V Foundation Scholar Award; a Columbia University RISE award; a Tara Miller Young Investigator Award by the Melanoma Research Alliance; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the AIM at Melanoma Foundation; the American Cancer Society; the Melanoma Research Alliance; Cancer Fighters of Houston; the Anne and John Mendelsohn Chair for Cancer Research; philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson; a PhRMA Foundation Predoctoral Fellowship; a Melanoma Research Alliance Senior Scientist Award; the William M. Scholl Chair for Cancer Research; and the German Federal Ministry of Education and Research (BMBF 01ZZ2004).
The full list of declarations of interest are listed in the online paper.