Analyzing the microenvironment

BAR HARBOR, Maine—Glioblastoma multiforme (GBM), the most common and most aggressive of the primary brain tumors, is highly malignant. These tumors infiltrate the brain extensively and may become enormous before symptoms appear. While GBM rarely metastasizes to the spinal cord or outside the nervous system, it is among the most deadly malignant primary brain tumors in adults.

The Jackson Laboratory (JAX), an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, has studied GBM for many years. A JAX-led research team has revealed the intrinsic gene expression patterns of GBM tumors, insights that could drive more effective treatments for GBM. JAX professor Dr. Roel Verhaak is the senior author of a paper published in Cancer Cell showing tumor gene expression patterns distinct from those of the surrounding immune cells, and characterizing the effects of chemotherapy and radiation treatments.

Verhaak, who heads a computational cancer biology lab with a research focus on the analysis of cancer genomics data to improve the understanding of cancer biology, was the first author of a landmark 2010 paper in Cancer Cell that established four subclasses of GBM—proneural, mesenchymal, neural and classical—based on molecular markers found in patient tumors. That paper was widely influential in the glioblastoma research field, according to Verhaak.

He added, “However, these four subtypes have not translated into differential treatment strategies. Every glioblastoma patient receives essentially the same treatment. We hope that our latest work will improve understanding of how to optimally stratify patients, another step towards precision medicine and more targeted, effective treatments.”

The microenvironment—or cells surrounding a tumor—consists of immune cells, supporting cells and other normal cells. Tumors that are donated to tissue banks include a mixture of microenvironment cells and cancer cells.

The researchers, who have a specialized research interest in understanding disease progression of brain tumors, especially glioblastoma and glioma, isolated the intrinsic gene expression pattern of 364 GBM tumors and observed the impact of the standard cancer treatment regimens of temozolomide and radiation on the gene expression patterns on both the remaining tumor and non-tumor cells, after subtracting out the effects of therapy on the tumor-associated non-cancer cells.

“By separating out the contributions of the microenvironment, we developed a much clearer picture of the ‘ecosystem’ of hundreds of tumors,” said Verhaak. “We determined what types of cells are in the microenvironment and what their contributions are, and also assessed how treatment affects the microenvironment as well as the tumor cells themselves.”

Through this approach, the team also found that the molecular markers previously defining the neural subtype of GBM was actually ascribed to the presence of normal neural tissue in the tumor margin, thus not characteristic of the actual tumor subtype. By studying gene expression patterns in glioblastomas after treatment, their analysis also revealed that the presence of macrophages correlates with poorer outcomes for GBM patients receiving radiation therapy and that tumors with a relatively high number of point mutations have an increased number of positive (CD8+) T cells, indicating they could respond to checkpoint inhibitors.

The resulting gene expression datasets, which are publicly available to researchers, provide comprehensive profiles of glioblastoma characteristics to more accurately guide immunotherapy trials. The researchers believe that their study “defines a strategy to determine transcriptional subtype and associates expression subtypes to the tumor-associated immune-environment.” They believe that their research “may aid in the application of immunotherapy approaches in a disease type with very limited treatment options.”

Support for this research came from the National Institutes of Health, the Cancer Prevention & Research Institute of Texas, University Cancer Foundation via the University of Texas MD Anderson Cancer Center University Cancer Foundation, the National Brain Tumor Association's Defeat GBM project, National Brain Tumor Association Oligo Research Fund, the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare of the Republic of Korea, the Seve Ballesteros Foundation and the American Cancer Society.