Plain language summary: Engineered extrachromosomal oncogene amplifications promote tumorigenesis
Below is a plain language summary of Engineered extrachromosomal oncogene amplifications promote tumorigenesis, a paper published in Nature in December 2024 by Cancer Grand Challenges team eDyNAmiC.
It has been co-developed by the team eDyNAmiC patient advocates. It was written by Shirin Khalili and Katell Maguet based on first draft versions written by the first authors of the paper.
Closing the circle: how to multiply genes in cells and mice
Renowned physicist Richard Feynman once said, "What I cannot create, I do not understand," and this principle applies to many fields of science, including cancer biology.
In normal cells, DNA is neatly organised into 23 pairs of chromosomes each having thousands of genes that control cell growth and function. However, in cancer cells, certain genes that control cell division or survival become more active due to changes in DNA structure, pushing cells to grow and multiply abnormally quickly.
Cancer is caused by changes—also known as mutations—in two types of genes:
- Tumor suppressor genes, which help suppress cancer formation.
- Oncogenes, which promote cancer formation.
Since the 1980s, researchers have developed methods to make these mutations in cells and animals, such as mice, to study how they affect cancer. These techniques have been crucial for understanding how cancers develop, progress, escape the defence mechanisms that protect us, and eventually spread to other organs. They have also paved the way for the development and testing of new and more effective therapies.
However, one important type of gene mutation has been difficult to create in the lab: gene amplifications. In normal cells, most genes exist in two copies, one from each parent, on the 23 pairs of chromosomes. In the case of gene amplifications, a piece of DNA containing one or more genes is "multiplied" to more than 100 copies per cell. This can lead to cancer.
In some of the most aggressive human cancers, these amplifications happen through the accumulation of hundreds of copies of extrachromosomal DNA molecules (ecDNAs). ecDNA molecules are loop-shaped and because of their unique biology, they make it possible for cancer cells to turbo-charge the machinery that drives their growth and ability to become resistant to treatment. Patients with ecDNA-positive cancers have worse outcomes than patients with ecDNA-negative cancers.
In this study, we show how to create gene amplifications with ecDNAs in both cells and mice. We also demonstrate how this strategy can be combined with fluorescent tags to track cells containing the created ecDNAs over time.
What's more, we show that when this is done in mice, it can enhance the formation and worsening of cancer.
Why is this important, and how does it benefit cancer patients?
This research is an important step toward developing new therapies specifically targeting cancers that contain ecDNAs. By enabling scientists to study cancer progression driven by ecDNAs in a living animal—something previously impossible—this approach will speed up drug discovery to treat ecDNA-positive cancers and advance our understanding of this important type of mutation.
