Discovery of Extrachromosomal DNA Acting Like a Secret Agent Opens New Horizons in Cancer Treatment

Extrachromosomal DNA (extra-chromosomal DNA, ecDNA) consisted of largely overlooked cellular DNA fragments until recently, with no clear understanding of what these tiny elements did. A new study found that ecDNA has a crucial role in cancers developing drug resistance and spreading.

Extrachromosomal DNA (ecDNA) consists of DNA fragments outside the chromosomes within cells. While chromosomes determine a cell’s normal structure and function, ecDNA is stored outside them. It can multiply during cell division and contain different genetic material outside chromosomes. It can therefore carry oncogenes and other cancer-associated genetic alterations, allowing tumors to become resistant to cancer drugs.

A Discovery That Could Change Cancer Treatment

Blocking the activity of these DNA fragments, which can occur inside or outside the nucleus, is thought to have potential for breakthroughs against some aggressive cancers. The study discussed here, published in Nature Genetics, observed that ecDNA can separate itself from a chromosome and exhibit gene behavior capable of causing cancer.

In the scanning electron micrograph above, inside a cancer-cell nucleus, normal chromosomes are marked by blue arrows and circular extrachromosomal DNA by orange arrows. (Source: Paul Mischel, UC San Diego)

Previous research showed that certain genes can lose function or become activated, causing uncontrolled cell division and tumors. Genes capable of causing cancer when their normal function changes are called oncogenes.

For cells to function normally, genes in DNA must be activated in a particular sequence, and newly divided cells must be functional. Oncogene activation or increased copy number disrupts normal function, and cells begin dividing abnormally.

Oncogenes as Key Players in Treatment Resistance

Oncogenes are important as a cause of resistance to cancer treatment. During drug treatment, they can replace proteins lost or inactivated within the cell, allowing cancer-causing behavior to continue. Completely eliminating oncogenes or their effects may therefore help create more effective treatment.

Oncogenes Hide Inside ecDNA

The researchers showed that oncogenes evade cancer drugs, disappearing within cells during drug interactions and hiding in ecDNA. Their ability to reappear when treatment stops and adapt to any conditions highlights the importance of understanding ecDNA structure. The researchers emphasize that the next step is eliminating ecDNA and developing drugs to disrupt the function of proteins in its structure.

Oncogenes can replace proteins that disappear or become inactive, allowing a cell’s cancer-causing behavior to continue. Drugs disrupting protein function within ecDNA may therefore help produce more effective treatment.

The Role of Extrachromosomal DNA in Early-Onset Cancers

Cancer, as we know, results from accumulating defects in DNA. This is why age is the most important cancer risk factor. If so, why do children get cancer and what differs in the mechanisms of early-onset cancers? ecDNA holds important answers to these questions.

ecDNA is among the structures enabling rapid evolution in childhood and early-onset cancers. It is a separate fragment of cancer-cell DNA that circulates between cells and is not replicated through inheritance like normal chromosomes. This allows rapid adaptation and treatment resistance. Pioneering cancer researcher and physician Paul Mischel and colleagues are investigating its role in these cancers, work that could help develop more effective treatments.

Catching the Mastermind Behind Cancer Evolution

Cancer cells undergo rapid evolutionary changes.

Paul Mischel and colleagues’ findings show that extrachromosomal DNA enables rapid cancer-cell evolution and treatment resistance. Oncogenes can replace proteins that disappear or become inactive, allowing cancer-causing behavior to continue. This indicates that rapidly multiplying ecDNA outside the chromosomes is central to cancer evolution and treatment resistance.

An ecDNA Subtype Is Also Drawing Attention: eccDNA

eccDNA (extrachromosomal circular DNA) is a subtype of ecDNA, describing extra DNA within cells in a circular form. Like ecDNA, it can cause cancer cells to evolve rapidly and resist treatment.

Both terms help explain rapid cancer-cell evolution and resistance, playing important roles in cancer genetics and treatment.

Unlike large ecDNA, small eccDNA is much more widespread. Advances have begun to show that eccDNA occurs more often in human cells than previously thought and may have important functions, thanks to improvements in DNA sequencing techniques. Its theoretical roles include:

• Genetic heterogeneity and tumor evolution in cancer, particularly amplification of oncogenes and drug-resistance genes;
• Expression of regulatory RNAs;
• Acting as molecular sponges for transcription factors;
• Intercellular communication;
• The aging process;
• Activation of the innate immune system

eccDNA is not long enough to contain protein-coding genes but is long enough to encode regulatory RNAs. microDNA(the name for circular DNA of 100-1000 base pairs within the eccDNA class) can act as molecular sponges (one molecule capturing and trapping another to eliminate its effects; capturing transcription factors indirectly controls gene expression). Kumar P. and colleagues showed that microDNA occurs as circulating DNA in human blood. Its greater stability than linear DNA suggests potential use in liquid biopsies as a biomarker. The key challenge is distinguishing circular DNA released by cancer cells from that released by normal cells in a cell-free environment such as plasma or serum. Another important point is that if other cells take up and process this microDNA, it could add a new pathway for intercellular communication.

Conclusion

The study clearly shows that extrachromosomal DNA can carry oncogenes and make tumors resistant to cancer drugs. It also describes how oncogenes can disappear from the cell, hide in ecDNA and reappear when cancer treatment becomes ineffective. It opens new horizons for ecDNA as an important future cancer-treatment target.