Brain Tumour Progression Driven by Stem-Like Cell Changes, Study Finds

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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 to illuminate cancer development and could inform future treatments and prognostic measures for gliomas.

The researchers published their findings on 22nd June in Nature Genetics. They applied advanced single-cell profiling techniques and computational analysis tools to primary and recurrent tumour samples from patients with a form of glioma called IDH glioma. These tumours affect young adults and are driven by mutations in enzymes called isocitrate dehydrogenases (IDH).

IDH gliomas typically originate as slow-growing tumours 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. IDH-mutant gliomas represent a distinct category of brain tumours that typically occur in younger adults compared with more aggressive forms such as glioblastoma. The initial slow growth gives patients a period of relative stability, but eventual progression to higher-grade disease remains a major clinical challenge.

“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,” said Dr Dan Landau, an oncologist at NewYork-Presbyterian and Weill Cornell Medical Center.

The study’s other co-senior author is Dr Mario Suvà, a professor in the Department of Pathology and Krantz Family Center with Mass General Brigham. 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 analysing 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 tumour samples that included samples taken at different times, at lower- and higher-grade stages of cancer, 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 methylation, DNA mutations, and gene activity patterns tend to change in these tumours over time. For the first time, using single-cell, multi-modality profiling techniques rather than traditional bulk-tissue analysis, the results showed that IDH glioma progression is invariably associated with low DNA methylation levels across all cancer cells. The new single-cell insights reveal uniform hypomethylation patterns across malignant cells in progressed tumours, supporting its role as a driver rather than a mere consequence of increased stem-like states.

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 behaviour, including the aberrant un-silencing of genes meant to be active only in neural stem cells. Experts note that such detailed mapping of tumour evolution at the single-cell level marks a significant advance in understanding how epigenetic changes influence cancer cell behaviour. By integrating DNA methylation profiling with gene expression data, the study highlights specific pathways, such as altered regulation of genes involved in neural stem-cell programmes, that contribute to tumour plasticity and treatment resistance.

“This is one of the first studies 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,” Dr Suvà said.

The research team’s multi-omic approach provides a comprehensive view that could guide the development of new prognostic tools. Measuring methylation levels more precisely in clinical settings might help predict which patients are at higher risk of rapid progression. It could also inform strategies to counteract hypomethylation effects or enhance the efficacy of existing IDH inhibitors.

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 various grants. Additional support came from the STARR Cancer Consortium, The Mark Foundation Emerging Leader Award, The Sontag Foundation Distinguished Scientist Alumni Award, the MacMillan Family Foundation, and the MacMillan Center for the Study of the Non-Coding Cancer Genome at the New York Genome Center.

The findings underscore the value of advanced genomic technologies in dissecting complex cancer biology. As researchers continue to refine these methods, similar approaches may yield breakthroughs in other hard-to-treat malignancies where cell state transitions drive disease worsening.