Researchers at the Shenzhen Institutes of Advanced Technology (SIAT) have taken that lead, all the way to the end of the marathon. Most recently, they are pushing our understanding of ecDNA (extrachromosomal DNA). This special type of circular DNA, found outside of typical chromosomes, is key for many types of cancer. Specifically, led by Professor Gan Haiyun, the team used state-of-the-art CRISPR technology to establish two ecDNA-positive (ecDNA+) cell models for further studies. Their study uncovers a deeper understanding of how ecDNA is maintained. Moreover, it investigates the association of ecDNA and the DNA damage response (DDR).
Based on their findings, the research team determined there is a reciprocal regulatory relationship between ecDNA maintenance and DDR. This observation indicates that how cells perceive and handle ecDNA can profoundly alter their sensitivity to DNA damaging agents. By examining how ecDNA actively replicates and is stably maintained in ecDNA+ cells, the researchers have opened new avenues for cancer research and treatment.
Understanding Extrachromosomal DNA
Extrachromosomal DNA may be understood as a fluid double stranded circular DNA macromolecule independent of axially associated canonical chromosomal DNA architecture. Unlike typical genetic material, ecDNA is more dynamic and actively replicates within select cancer cells, enabling them to grow and survive. The remarkable stability of ecDNA in these cells, as mentioned above, enables it to drive a multitude of oncogenic processes.
In their study, Professor Gan and his team primarily targeted their attention on the preservation of ecDNA inside tumor cells. To understand the effects of ecDNA, they developed two custom cell models that overexpress ecDNA. In this study, they used the gene-editing tool CRISPR to impose their will on multiple genetic influencers. This daring approach uncovered new layers to how ecDNA’s persistence mechanisms are maintained.
“Our work provides insights into DDR’s role in ecDNA dynamics and evolution. It shows that ATM-mediated DDR and alt-NHEJ are critical for ecDNA persistence in some cancers although more research is needed to understand ecDNA’s effects on tumor heterogeneity, progression, and drug resistance. Targeting these pathways may offer new strategies for the diagnosis, prognosis, and treatment of ecDNA-driven tumors,” – Prof. Gan.
Implications of the Research Findings
These results indicate that blocking major alternative non-homologous end joining (alt-NHEJ) components prevents ecDNA circularization. One key player is LIG3, which has an important hand in this process. This disruption is an important event. It results in a profound decrease in ecDNA content inside tumor cells. Therefore, elucidating these pathways could yield novel approaches to diagnose and treat ecDNA-driven cancers.
This research shows how targeting ecDNA pathways may be a new way to extend cancer survival outcomes. By manipulating these pathways, clinicians would be able to tap into novel therapies designed specifically for tumors using ecDNA as their lifeline. This discovery indicates a hopeful path for cancer therapies to come.
Future Directions in Cancer Research
Geneticist Xing Kang and his team recently published one of the first studies on ecDNA. That research has now been published in the journal Cell, representing a big step forward for cutting edge cancer research. Dissecting the complex interplay between ecDNA maintenance and DDR will be key for driving future therapeutic approaches to their efficacy.
At the moment, several research labs are investigating the complex dynamics of ecDNA. They hope to find out its entire effect on tumor heterogeneity, progression, and drug resistance. The reciprocal interplay between ecDNA maintenance and DDR has the power to revolutionize our approaches to cancer diagnosis and treatment.