March 2025

NEUROSCIENCES

STUDY ESTABLISHES CELL DEATH AS A DRIVING FORCE IN GLIOBLASTOMA

Featuring: Daniel J Brat, MD, PhD​

Cell death has been found to be a driving factor in glioblastoma progression, according to a Northwestern-Medicine-led study published in the Proceedings of the National Academy of Sciences.

Glioblastoma, one of the most aggressive and lethal brain cancers, has a five-year survival rate of only 6.9 percent, according to the National Brain Tumor Society.

​While the relationship between glioblastoma and cell death, also called necrosis, has been established, it had remained unclear whether it contributed to cancer growth or was merely a byproduct of the disease, said Daniel J Brat, MD, PhD, chair and the Magerstadt Professor of Pathology, who was senior author of the study.

“There’s a common phrase in textbooks that the cancer is growing so wildly, so out of control, that it outgrows its blood supply and that the necrosis, the cell death, is an indicator of just how out of control the cancer is. I’ve always thought that was a little bit fishy,” said Brat, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “I think the development of necrosis is a tipping point for this disease. It’s been known for over a hundred years to be the feature under the microscope that correlates with the worst patient outcomes. And so far, nobody has really understood why that is.”

​​In the study, investigators observed the progression of glioblastomas in mice. First, the authors focally blocked blood flow to the tumor within a single blood vessel. By using advanced intravital microscopy, the investigators found that tumors cut off from their blood supply in their center rapidly increased in size and dramatically increased the number of pro-tumor immune and stem cells.

This research suggests that necrosis is not merely a byproduct of aggressive tumor growth but rather an active contributor to growth and changes within the tumor, Brat said.

“What we showed is that the development of necrosis in the middle of these gliomas incites this outward expansion,” Brat said. “It’s actually not the cancer outgrowing its blood supply, it’s the compromised blood supply reshaping the tumor microenvironment so that it has this outward growth that’s very rapid.”

The findings provide a new model for scientists to study glioblastoma, Brat said, and his laboratory will continue to use it to uncover new insights about how the cancer progresses.
Central thrombosis and initial necrosis, with surrounding single-cell glioma migration patterns viewed by two-photon microscopy
Central thrombosis and initial necrosis, with surrounding single-cell glioma migration patterns viewed by two-photon microscopy. Courtesy of the Brat laboratory.
“I intend to use this model to study much more in depth over the coming years,” Brat said. “There’s stem cell enrichment, new blood vessel formation and a complete change in the immune landscape following the development of necrosis. All of those things can now be studied with this model.”

Jiabo Li, MD, PhD, a postdoctoral scholar in the Brat laboratory, and Ling-Kai Shih, a student in the Northwestern University Interdepartmental Neuroscience (NUIN) Ph.D. program, were first authors of the study.

The study was supported by National Institute of Health grants R01CA247905, R01CA214928, R21AG086751 and P50CA221747.

This article was originally published in the Feinberg School of Medicine News Center on March 27, 2025. 
Daniel J Brat, MD, PhD, chair and the Magerstadt Professor of Pathology, was senior author of the study.
​
Jiabo Li, MD, PhD, a postdoctoral scholar in the Brat laboratory, was co-first author of the study.

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