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Recent research from Weill Cornell Medicine indicates that the structural arrangement of DNA within brain cells may provide crucial insights into glioblastoma, a particularly aggressive type of brain cancer. Published on April 3 in Molecular Cell, this study introduces a novel perspective on cancer that focuses not only on genetic mutations but also on the spatial organization and regulation of genes within a three-dimensional framework.
“Glioblastoma represents one of the most challenging and untreatable cancers. While advances have been made in mapping the mutations and genes associated with it, effective treatments remain elusive,” acknowledged Dr. Effie Apostolou, an associate professor of molecular biology in medicine at Weill Cornell and a co-leader of the study. “This study brings a new viewpoint to the forefront, offering potential pathways for understanding the regulatory mechanisms underlying this cancer and identifying targets that could be leveraged for treatment.”
The study highlights a fundamental contrast in the physical dimensions of the human genome. While DNA can stretch to about six feet in length, it must fit into the nucleus of a cell, which is significantly smaller, about 80 times less than a grain of sand. This compression requires the DNA to fold extensively, gathering regions that are distantly located along the linear strand. “By analyzing the 3D configuration of DNA, we discovered interaction hubs where various genetic elements, seemingly unconnected, are actually able to communicate and coordinate,” stated Dr. Apostolou.
In normal cellular conditions, these hubs usually facilitate vital physiological processes, such as embryonic development. However, the study found that in glioblastoma cells taken from various patients, there is a clustering of genes associated with cancer, which coordinate with other genes not typically involved in this form of tumor.
“The research illustrates how the three-dimensional organization of DNA within tumor cells significantly influences the behavior of brain cancer, at times surpassing the role of genetic mutations,” commented 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 Dr. Sarah Breves, affiliated with Dr. Apostolou’s lab and a surgical resident, along with Dr. Dafne Campigli Di Giammartino from the Instituto Italiano di Tecnologia in Genoa, Italy, contributed significantly to this research.
The Role of 3D Gene Hubs in Cancer Progression
Typically, in a healthy individual, the DNA regions linked to glioblastoma hubs remain inactive, meaning the associated genes do not produce proteins that affect cellular function. The researchers explored the effects of silencing a suspected cancer-related hub in glioblastoma cells. Utilizing tumor samples from consenting patients at NewYork-Presbyterian/Weill Cornell Medical Center, they pursued their investigation.
Employing CRISPR interference, a gene-editing tool, they successfully disabled the hub in glioblastoma cells cultured in petri dishes, initiating a cascade of effects. This action led to a decline in the activity of numerous genes associated with the hub, disrupting multiple cancer-related genes and diminishing the cancer cells’ ability to aggregate and form tumor-like structures. “We managed to influence the oncogenic programming of glioblastoma cells and their propensity to develop cancerous characteristics in vitro,” said Dr. Apostolou.
Implications Beyond Glioblastoma
Motivated by their findings in glioblastoma, the researchers expanded their analysis to include 16 different cancer types from prior studies. They identified that hyperconnected 3D hubs are common across various cancers including melanoma, lung, prostate, uterine, and others. Although specific hubs differ from one cancer to another, many are found to overlap among multiple cancer types.
Significantly, the majority of these 3D hubs do not arise from clear genetic mutations such as DNA damage or rearrangements; rather, they often emerge due to epigenetic modifications—changes in DNA packaging and gene regulation. For example, the protein machinery that interacts with specific DNA regions and influences gene activation plays a crucial role in the formation of these hubs.
“By pinpointing these pivotal control hubs within the 3D structure of the genome, we have identified new potential therapeutic targets,” remarked Dr. Fine, who also serves as the associate director for translational research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “Our next steps will involve investigating how these hubs are established and whether we can effectively disrupt them to impede or halt tumor growth. This research indicates that targeting the spatial arrangement of the genome and its epigenetic features may enhance traditional treatment approaches.”
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