A study led by investigators at Weill Cornell Medicine, the New York Genome Center, Harvard Medical School, and Mass General Brigham reports on Jul. 11 that a form of glioma, a type of brain cancer, tends to become more malignant as glioma cells increasingly transform into immature, stem-cell-like states. The research team used advanced single-cell-profiling techniques and computational analysis tools on primary and recurrent tumor samples from patients with IDH glioma.
IDH gliomas affect young adults and are driven by mutations in isocitrate dehydrogenases (IDH) enzymes. These tumors usually begin as slow-growing masses with high levels of gene-silencing methylation marks on DNA but later lose many of those marks as they progress to faster-growing and more aggressive forms. The analysis indicated that this progressive hypomethylation led to an increased presence of immature, hard-to-kill cell states within the tumor.
"These tumors become more aggressive in the brain, and more difficult to treat," said Dr. Dan Landau, co-senior author of the study and Bibliowicz Family Professor of Medicine at Weill Cornell. "The approach we took in this study gives us the kind of detailed picture of this process that we've long sought but never had before." Dr. Landau is also a core faculty member at the New York Genome Center and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Drs. Landau and Mario Suvà have developed advanced methods for recording multiple layers of information in individual cells and analyzing large datasets from these records. In this study, their approach was applied to 36 tumor samples taken at different times from patients who provided informed consent. The researchers mapped typical IDH-glioma development from low- to high-grade tumors using single-cell multi-modality profiling techniques for the first time instead of traditional bulk tissue analysis.
The findings showed that progression in IDH gliomas is invariably associated with lower DNA methylation levels across all cancer cells. This hypomethylation was linked to a higher frequency of stem-like glioma cells—cells known for their plasticity and ability to spread invasively within tissues—through mechanisms such as aberrant un-silencing of genes typically active only in neural stem cells.
Dr. Landau said these results might help explain why an IDH-inhibitor drug used for treating IDH gliomas seems effective only for some patients, said Dr. Landau. "A possibility we hope to investigate in future research is that the non-responding gliomas have more hypomethylation, which makes it harder for the drug to work."
