Glioblastoma may be driven by 3D DNA folding patterns, not just mutations, offering new paths for treatment.
A new preclinical study from researchers at Weill Cornell Medicine suggests that the way DNA folds inside the nuclei of brain cells could play a crucial role in understanding glioblastoma, a particularly aggressive and lethal form of brain cancer. Published in Molecular Cell, the findings propose a novel framework for studying cancer, one that goes beyond genetic mutations to focus on the spatial organization and regulatory interactions of genes in three dimensions.
“Glioblastoma is one of the most aggressive and incurable tumors. Although we know a lot about the mutations and the genes that characterize it, we still have no effective ways to stop it,” said Dr. Effie Apostolou, associate professor of molecular biology in medicine at Weill Cornell, who co-led the study. “Now, we’re bringing a fresh perspective to the problem. We may have a chance of figuring out the regulatory logic of this cancer and identifying potential control centers that we can target to eliminate it.”
The new perspective involves a basic dichotomy: The human genome, if fully extended, measures about six feet in length. Yet, it must be compacted to fit inside the cell’s nucleus, a space roughly 80 times smaller than a grain of sand. To achieve this, the DNA folds and loops repeatedly, allowing distant regions along the linear sequence to come into close physical contact.
“By examining the DNA organization in the 3D space, we uncovered hubs where multiple genetic regions that look like they should be disconnected are actually able to communicate and work together,” said Dr. Apostolou.
In a healthy person, hubs coordinate normal physiological processes like embryonic development. But when the researchers analyzed glioblastoma cells from different patients, they found that cancer-causing genes clustered together and coordinated with other genes that were not known to be involved in glioblastoma.
“This study shows that the 3D organization of DNA inside tumor cells plays a powerful role in driving brain cancer behavior—sometimes even more than mutations themselves,” said Dr. Howard Fine, the Louis and Gertrude Feil Professor of Medicine in Neurology at Weill Cornell Medicine and director of the Brain Tumor Center at NewYork-Presbyterian/Weill Cornell Medical Center, who co-led the study.
Co-first authors on the study included Dr. Sarah Breves, who works in Dr. Apostolou’s lab and is a surgical resident at NewYork-Presbyterian/Weill Cornell Medical Center, and Dr. Dafne Campigli Di Giammartino at the Instituto Italiano di Tecnologia in Genova, Italy.
3D Gene Hubs: Form Dictating Function
In healthy people, the DNA regions involved in glioblastoma hubs are usually quiet, meaning the cell does not use the genes in their vicinity to produce proteins that impact how the cell functions. The researchers wondered what would happen to glioblastoma cells if they silenced a suspected cancer-related hub. With consent from patients undergoing treatment at NewYork-Presbyterian/Weill Cornell Medical Center, they obtained the cells from tumor samples for the study.
When they used a gene editing tool called CRISPR interference to shut down the hub in the glioblastoma cells growing in petri dishes, it triggered a domino effect. The activity of many hub-connected genes dropped, multiple cancer genes were disrupted and the cancer cells reduced their ability to form tumor-like spheres. “We were able to alter the oncogenic program of glioblastoma cells and their ability to organize and form something like cancer in the dish,” Dr. Apostolou said.
Not Just About Brain Cancer
The findings in glioblastoma prompted the researchers to examine previously published analyses of 16 different cancer types. They discovered that these hyperconnected 3D hubs appear to be a feature of most cancers, including melanoma, lung, prostate, uterine, and others. Although each cancer has a unique set of hubs linked, they also found hubs shared across multiple cancer types.
The team observed that the majority of 3D hubs aren’t caused by obvious genetic mutations like broken, amplified, or rearranged DNA. Instead, they often form because of epigenetic changes—alterations in how DNA is packaged and how genes are controlled in the cell. For instance, the protein machinery that binds to specific DNA sequences and influences whether a gene is turned on or off impacts the formation of the 3D hubs.
“By identifying key control hubs in this 3D structure, we’ve uncovered new potential targets for future treatments,” said Dr. Fine, who is also associate director for translational research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “Next, we will explore how these hubs form and whether we can safely disrupt them to slow or stop tumor growth. Our research suggests that targeting the epigenetic and spatial genome organization could complement traditional molecular therapies.”
Reference: “Three-dimensional regulatory hubs support oncogenic programs in glioblastoma” by Sarah L. Breves, Dafne Campigli Di Giammartino, James Nicholson, Stefano Cirigliano, Syed Raza Mahmood, Uk Jin Lee, Alexander Martinez-Fundichely, Johannes Jungverdorben, Richa Singhania, Sandy Rajkumar, Raphael Kirou, Lorenz Studer, Ekta Khurana, Alexander Polyzos, Howard A. Fine and Effie Apostolou, 26 March 2025, Molecular Cell.
DOI: 10.1016/j.molcel.2025.03.007
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