Cancer cells with extra chromosomes rely on these chromosomes for tumor growth. The research suggests that removing these extra chromosomes could inhibit tumor formation, presenting a potential new approach for cancer treatment.
Human cells typically possess 23 pairs of chromosomes; the presence of extra chromosomes is known as aneuploidy.
“If you look at normal skin or normal lung tissue, for example, 99.9% of the cells will have the right number of chromosomes. But we’ve known for over 100 years that nearly all cancers are aneuploid,” said Jason Sheltzer, assistant professor of surgery at Yale School of Medicine and senior author of the study.
The role of extra chromosomes in cancer—whether they cause cancer or result from it—has been unclear.
“For a long time, we could observe aneuploidy but not manipulate it. We just didn’t have the right tools,” said Sheltzer, who is also a researcher at Yale Cancer Center.
“But in this study, we used the gene-engineering technique CRISPR to develop a new approach to eliminate entire chromosomes from cancer cells, which is an important technical advance.
Being able to manipulate aneuploid chromosomes in this way will lead to a greater understanding of how they function.”
Former lab members Vishruth Girish, now an M.D.-Ph.D. student at Johns Hopkins School of Medicine, and Asad Lakhani, now a postdoctoral researcher at Cold Spring Harbor Laboratory, co-led the study.
The researchers used their newly developed approach, termed Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT), to target aneuploidy in melanoma, gastric cancer, and ovarian cell lines.
They specifically removed an aberrant third copy of the long portion (the “q arm”) of chromosome 1, which is associated with several cancer types, disease progression, and early cancer development.
“When we eliminated aneuploidy from the genomes of these cancer cells, it compromised the malignant potential of those cells and they lost their ability to form tumors,” said Sheltzer.
The researchers proposed that cancer cells may have an “aneuploidy addiction,” akin to “oncogene addiction,” a concept from earlier research that showed eliminating oncogenes disrupts cancers’ tumor-forming abilities.
In examining how an extra copy of chromosome 1q promotes cancer, the researchers found that multiple genes stimulate cancer cell growth when overrepresented due to their encoding on three chromosomes instead of the usual two.
This overexpression of certain genes revealed a vulnerability that might be exploited to target cancers with aneuploidy. Previous research indicated that a gene on chromosome 1, UCK2, is necessary to activate certain drugs.
The study found that cells with an extra copy of chromosome 1 were more sensitive to these drugs because of UCK2 overexpression.
This sensitivity suggested that the drugs could redirect cellular evolution away from aneuploidy, allowing a cell population with normal chromosome numbers and less potential to become cancerous.
In a mixture of 20% aneuploid cells and 80% normal cells, aneuploid cells dominated, making up 75% of the mixture after nine days. However, when exposed to a UCK2-dependent drug, aneuploid cells comprised only 4% of the mix after nine days.
“This told us that aneuploidy can potentially function as a therapeutic target for cancer,” said Sheltzer. “Almost all cancers are aneuploid, so if you have some way of selectively targeting those aneuploid cells, that could, theoretically, be a good way to target cancer while having minimal effect on normal, non-cancerous tissue.”
Further research is necessary before this approach can be tested in clinical trials. Sheltzer aims to move this work into animal models, evaluate additional drugs and other aneuploidies, and collaborate with pharmaceutical companies to progress toward clinical trials.
“We’re very interested in clinical translation,” said Sheltzer. “So we’re thinking about how to expand our discoveries in a therapeutic direction.”
