by Douglas Chung
Resistance to chemotherapy is a major problem facing many cancer patients. How do tumours develop drug resistance and adapt to changing environments within our bodies? One of the ways is through a novel type of DNA called extrachromosomal DNA (ecDNA).
Not all cells within a tumour look the same
A distinctive property of tumours that allows them to survive and adapt to their environment is that they are composed of cancer cells that are distinctly different from each other. This is termed tumour heterogeneity.
Imagine if a child was instructed to eat only a single colour of jelly beans from a jelly bean jar each day. A jar with only one colour of jelly beans (e.g. blue) would be emptied first, but a jar with a multitude of jelly-bean-colours would take much longer to finish. Similarly, tumours that have many subpopulations of cells (more jelly bean colours), are more likely to adapt to changing environments. These tumours are likely to survive and persist after a single cancer drug therapy.
Tumour heterogeneity is important for development of drug resistance
When a tumour is treated with a drug, some cancer cells will be unresponsive to the drug and continue to survive and replicate. From the above analogy, these cells are the jelly-beans that are not blue.
If you were to give this jar to a blue-jelly-bean-eating-child a second time, the number of jelly beans in the jar will not change. The tumour will persist, because now it has evolved to contained cancer cells that are resistant to the drug therapy. Therefore, tumours with a more diverse range of cell populations can develop resistance to a single drug. This is why it is common for certain tumours to be treated with a combination of cancer therapies.
To understand how tumours develop resistance to drug therapies, researchers are working to understand what contributes to the development of tumour heterogeneity.
ecDNA are novel types of DNA found in tumours that contribute to tumour heterogeneity
DNA is a genetic instruction manual used for the construction of the different proteins that allow cells to function. In mammalian cells, DNA is known to be tightly packed within a chromosome. However, researchers recently identified a novel type of DNA that exists in a circular structure called extrachromosomal DNA (ecDNA).
In a recent publication in Nature, Kristen Turner and colleagues developed a software called ECdetect to detect small circular ecDNA in 117 tumour cell lines and 17 types of cancer. Using ECdetect, in parallel with whole-genome sequencing and molecular techniques, they found that nearly half of these cancers have ecDNA in their cells. Furthermore, ecDNA only exist in tumour cells and not healthy cells.
Researchers found that these novel ecDNA had more cancer-promoting DNA sequences, called oncogenes, compared to normal chromosomal DNA. These oncogenes are amplified more in the ecDNA, contributing to a more malignant and heterogenous tumour. The discovery of ecDNA has changed our understanding of cancer genetics, providing a novel way for the tumour to adapt to the changing environment. Further research is needed to investigate how exactly ecDNA leads to tumour heterogeneity and drug resistance, both which make tumours more difficult to treat.
Finally, ecDNA can be used as a marker to distinguish between what are tumour cells and what are healthy cells. This provides a potential for ecDNA to be used as an early cancer detection tool, and a potential target for drug therapies.
References
- Burrell, Rebecca A., Nicholas McGranahan, Jiri Bartek, and Charles Swanton. 2013. “The Causes And Consequences Of Genetic Heterogeneity In Cancer Evolution”. Nature501 (7467): 338-345. doi:10.1038/nature12625.
- Turner, Kristen M., Viraj Deshpande, Doruk Beyter, Tomoyuki Koga, Jessica Rusert, Catherine Lee, and Bin Li et al. 2017. “Extrachromosomal Oncogene Amplification Drives Tumour Evolution And Genetic Heterogeneity”. Nature543 (7643): 122-125. doi:10.1038/nature21356.
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