Extrachromosomal DNA (ecDNA) refers to small, circular pieces of DNA found within a cell’s nucleus, separate from its main chromosomes. Though known for decades, advanced technologies have revealed their widespread presence and implications, particularly in disease research.
The Nature of Extrachromosomal DNA
Chromosomes organize DNA into long, linear structures. In contrast, ecDNA molecules are circular and float freely within the nucleus. These circular structures vary in size, ranging from hundreds of base pairs to several megabases. They are not physically connected to the main chromosomal structures.
Formation and Amplification
The formation of ecDNA often begins with chromothripsis, a genomic event where a chromosome shatters into DNA fragments. These fragments then reassemble to form new circular DNA molecules. Some of these newly formed circular pieces, particularly those containing specific genes, become ecDNA.
A distinguishing feature of ecDNA is its capacity for rapid amplification. Unlike chromosomal DNA, which is precisely duplicated and segregated during cell division, ecDNA can replicate independently and segregate unevenly into daughter cells. This random distribution means that some cells can acquire many copies of a particular ecDNA molecule, while others receive fewer or none. This allows a cell to accumulate dozens to hundreds of copies of specific ecDNA circles.
Influence on Cancer Aggressiveness
EcDNA contributes to the aggressiveness of many cancers. These circular DNA molecules frequently carry oncogenes, which are genes that promote uncontrolled cell growth and division. EcDNA allows for the amplification of these oncogenes, leading to an overproduction of the proteins that drive tumor development. This heightened gene expression is further enhanced by the circular structure of ecDNA, which is associated with more accessible chromatin and elevated transcription rates compared to linear chromosomal DNA.
The uneven distribution of ecDNA during cell division fosters rapid tumor evolution and increased diversity within the tumor. As cells divide, some daughter cells may inherit a greater number of specific ecDNA copies, leading to varying genetic profiles even within the same tumor. This genomic plasticity allows cancer cells to adapt quickly to changing conditions, including therapeutic pressures, making the tumor more aggressive and resilient.
Challenges in Cancer Treatment
EcDNA poses challenges in cancer treatment, particularly in the development of drug resistance. During cell division, ecDNA molecules are segregated unevenly among daughter cells because they lack a centromere, which is a structure that ensures equal distribution of chromosomes. This unequal inheritance means that some daughter cells may acquire many copies of genes that confer drug resistance, while others receive none.
When a tumor is exposed to chemotherapy or targeted therapies, the cells that happen to inherit a high number of drug-resistance genes on their ecDNA are more likely to survive. These resistant cells can then rapidly multiply, leading to the repopulation of the tumor with a drug-resistant phenotype. This dynamic, adaptable mechanism allows cancers with ecDNA to quickly overcome treatment, leading to relapse and making effective long-term treatment difficult.
Targeting ecDNA for New Therapies
Current research efforts are actively exploring strategies to target ecDNA to improve cancer treatment outcomes. One approach involves developing drugs that interfere with ecDNA replication, aiming to prevent the uncontrolled amplification of oncogenes. Another strategy focuses on blocking the function of the oncogenes carried by ecDNA, thereby inhibiting the cancer-promoting proteins they produce. For instance, experimental drugs like BBI-2779 are being investigated for their ability to exploit instabilities in ecDNA-containing cancer cells, causing cell death.
Scientists are also exploring ways to eliminate ecDNA from cancer cells entirely or to prevent its reintegration into chromosomal DNA. For example, inhibiting the CHK1 protein has shown promise in selectively destroying ecDNA-containing cancer cells, particularly when combined with other targeted therapies. These ongoing investigations represent a frontier in cancer research, seeking to leverage the unique biology of ecDNA to develop novel and more effective therapeutic interventions.