A form of glioma, a type of brain cancer, tends to progress towards greater malignancy due to an increasing tendency of the glioma cells to transform into immature, stem-cell-like states, according to a study led by investigators at Weill Cornell Medicine, the New York Genome Center, Harvard Medical School and Mass General Brigham. The findings showcase the power of modern laboratory technology for illuminating cancer development and could inform future treatments and prognostic measures for gliomas.
The researchers, who published their findings on June 22 in Nature Genetics, applied advanced single-cell-profiling techniques and computational analysis tools to primary and recurrent tumor samples from patients with a form of glioma called IDH glioma. These tumors affect young adults and are driven by mutations in enzymes called isocitrate dehydrogenases (IDH). IDH gliomas typically originate as slow-growing tumors with an abnormally high amount of gene-silencing methylation marks on DNA but later lose many of those marks and become faster-growing and more aggressive. The analysis suggested that this progressive hypomethylation led to an increasing frequency of glioma cells in immature, hard-to-kill states.
"These tumors become more aggressive in the brain, and more difficult to treat," said study co-senior author Dr. Dan Landau, the Bibliowicz Family Professor of Medicine and a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell. Dr. Landau is also a core faculty member of the New York Genome Center and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. "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."
The study's other co-senior author is Dr. Mario Suvà, a professor in the Department of Pathology and Krantz Family Center for Cancer Research with Mass General Brigham Cancer Institute. The co-first authors are Drs. Masashi Nomura, Ramya Raviram and Joshua S. Schiffman.
Drs. Landau and Suvà have helped pioneer the development and use of advanced methods for recording multiple layers of information in individual cells, and for analyzing the resulting large, multi-dimensional datasets. Applying these tools to cancers, they have been mapping the evolution of malignancies in ever-finer detail , creating "ancestral trees" of cancers and revealing the drivers of progression.
In the study, the researchers applied this approach to a set of 36 tumor samples that included samples taken at different times, at lower and higher cancer grades, from the same patients. All patients provided informed consent for the study. The investigators used their new tools to map typical IDH-glioma development from low to high grades, showing how DNA methylations, DNA mutations and gene activity patterns tend to change in these tumors over time. For the first time using single-cell, multi-modality profiling techniques—as opposed to traditional bulk tissue analysis—the results showed that IDH glioma progression is invariably associated with low DNA methylation levels across all cancer cells.
The analysis linked this hypomethylation to an increased frequency of stem-like glioma cells. Stem cells in cancers are notorious for their ability to change their properties—a characteristic called plasticity—and spread invasively within tissues. The findings pointed to several potential mechanisms linking loss of methylation to more stem-like behavior, including the aberrant un-silencing of genes meant to be active only in neural stem cells.
"This is one of the first study that provides detailed information about why hypomethylation makes these gliomas worse," Dr. Suvà said.
He added that the results might help explain the observation that an IDH-inhibitor drug used to treat IDH gliomas—a drug that nudges glioma cells towards more mature, differentiated, slower-growing states—seems to benefit only a subset of patients.
"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," he said.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Dan Landau .
This work was supported in part by the National Cancer Institute and the National Human Genome Research Institute Center of Excellence in Genomic Science, both part of the National Institutes of Health, through grants numbers R01CA258763, R37CA245523, R01CA276765, R33CA267219 and RM1HG011014. Additional support was provided by the STARR Cancer Consortium, The Mark Foundation Emerging Leader Award, The Sontag Foundation Distinguished Scientist Alumni Award. This work was made possible by the MacMillan Family Foundation and the MacMillan Center for the Study of the Non-Coding Cancer Genome at the New York Genome Center.
