Theoretical physics helps uncover the molecular mechanisms of extrachromosomal DNA in tumors

New insights into the molecular mechanisms that regulate extrachromosomal DNA in tumors: This is the result of a study led by a research team from the National Institute of Nuclear Physics and the University of Naples Federico II, which used polymer physics models to explore the complex organization and behavior of extrachromosomal DNA. The study, which combines tools from molecular biology and theoretical physics to investigate the mechanisms involved in tumor processes, was recently published in *Nature Communications*.

Cancer cells can contain small circular DNA molecules located outside normal chromosomes, called ecDNA (extra-chromosomal circular DNA). ecDNA can carry oncogenes—genes involved in tumor development—along with regulatory elements, contributing to increased gene expression and, consequently, the growth of cancer cells as well as their resistance to therapies. Understanding the mechanisms governing the behavior of ecDNA is therefore of great interest to basic biomedical research.

“In our study, we used polymer physics models to describe the interactions between ecDNA and BRD4, a protein involved in the regulation of gene expression,” explains Mario Nicodemi, a researcher at INFN and professor at the University of Naples Federico II, who led the research. “Thanks to its ability to mediate interactions between DNA molecules and other proteins, BRD4 can promote the formation of biomolecular condensates—highly dynamic structures that serve to rapidly concentrate molecules and organize reactions—and which may therefore play a significant role in tumor evolution. Clarifying these interaction mechanisms is therefore of fundamental importance for understanding how to interfere with them, and thus inactivate oncogenes in these cancer cells,” concludes Nicodemi.

The study shows that these interactions lead to the spontaneous aggregation of ecDNA in the cell nucleus through a phase-separation process, inducing the formation of ecDNA condensates. Within these condensates, interactions between different ecDNA molecules bring specific oncogenes into contact with DNA sequences that promote their activation, increasing their activity far beyond what would be expected simply from the increased number of gene copies in the system. The model’s predictions regarding the structure of the condensates were confirmed in the laboratory by experimental data on cancer cells.

The research also analyzed the effects of JQ1, a molecule that interferes with the activity of the BRD4 protein and thus with the phase separation of ecDNAs. In this case as well, the model’s predictions—that JQ1 disperses the condensates and thus reduces the expression of ecDNA oncogenes—were experimentally confirmed.

The study thus demonstrates how theoretical physics can become a valuable tool for unraveling the mechanisms underlying the organization and activity of ecDNAs, opening new avenues for identifying targeted strategies to interfere with the processes that sustain their activity.

“Phase separation of ecDNA condensates establishes in-trans contact domains that boost selective MYC regulatory interactions”