Most cancers exhibit aneuploidy, but its functional significance in tumorigenesis is controversial. Recently, in a research report titled "Oncogene-like addiction to aneuploidy in human cancers" published in the international journal Science, scientists from Johns Hopkins University School of Medicine and other institutions found that cancer cells with extra chromosomes may rely on these chromosomes to fuel tumor growth. Eliminating these extra chromosomes prevents the cells from forming tumors. Related research results suggest that selectively targeting extra chromosomes may provide a new way to treat cancer.
Human cells typically carry 23 pairs of chromosomes, and the extra chromosome is an abnormality known as aneuploidy. Researcher Professor Jason Sheltzer said that if you look at normal skin or normal lung tissue, 99.9 per cent of the cells have the correct number of chromosomes. But we've known for 100 years that almost all cancers are aneuploid. However, researchers do not yet know exactly what role the extra chromosome plays in cancer development, such as whether it causes cancer or is caused by it.
For a long time, researchers could observe aneuploidy but were unable to manipulate it. Of course, researchers may just not have the right tools to manipulate it. But in this study, the researchers used the gene-editing technique CRISPR to develop a new way to eliminate entire chromosomes from cancer cells, and manipulating aneuploid chromosomes in this way may hopefully help scientists better understand their underlying function and importance. Using a new approach developed by the researchers, using Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT), the researchers were able to target aneuploidy in melanoma, gastric and ovarian cancer cell lines. Specifically, they were able to remove the abnormal third copy of chromosome 1q, which is found in many types of cancer, is associated with disease progression, and occurs early in cancer development.
When aneuploidy is eliminated from the genomes of these cancer cells, the malignant potential of these cells is impaired, and they lose their ability to form tumors. Based on these findings, the researchers believe that cancer cells may have "aneuploidy addictions." Previously, researchers found that eliminating oncogenes—key genes that turn cells into cancer cells—could disrupt cancer's ability to form tumors, a finding that has led to the emergence of a model of cancer growth known as "oncogene addiction". When investigating how exactly the extra copy of chromosome 1q drives cancer, the researchers found that when multiple genes are overexpressed, it stimulates cancer cell growth because these genes are coded and expressed on three chromosomes instead of the typical two. Overexpression of certain genes also pointed the researchers to a vulnerability that could be used to target aneuploid cancers.
Previous findings have shown that a gene called UCK2, encoded on chromosome 1, is required to activate the effects of certain drugs. In this study, the researchers found that cells with an extra copy of chromosome 1 were more sensitive to these drugs than cells with the normal two copies of chromosome 1 because the UCK2 gene was overexpressed. What's more, the researchers observed, this sensitivity means that the drugs can redirect the evolution of cells away from aneuploidy, thereby encouraging populations of cells to carry a normal number of chromosomes, making them less likely to become cancerous. When the researchers created a mixture of 20 percent aneuploid cells and 80 percent normal cells, they found that in the mixture, the aneuploid cells prevailed. After 9 days, it made up 75% of the mixture. When the researchers exposed 20 percent of the aneuploid mixture to the UCK2-dependent drug, aneuploid cells made up only 4 percent of the mixture after nine days. This may point to aneuploidy as a potential therapeutic target in cancer, and nearly all cancers are aneuploid. So if you have some way to selectively target these aneuploid cells, in theory, that might be a good way to target cancer with minimal impact on normal, non-cancerous tissue.
Taken together, the findings suggest that tumor cells may be dependent on specific aneuploidies, which may suggest that these "aneuploid addictions" may be targeted to aid in the development of novel cancer therapeutic strategies. In any case, more research may be needed before this approach can be tested in a clinical trial, and the researchers are now considering how to extend the current findings into a therapeutic direction.
Reference
1.Girish V, et al. Oncogene-like addiction to aneuploidy in human cancers. Science, 2023: eadg4521.