Eliminating Extra Chromosomes in Cancer Cells Prevents Tumor Growth

Cancer cells with extra chromosomes depend on those chromosomes for tumor growth, a new Yale study reveals, and eliminating them prevents the cells from forming tumors. The findings, said the researchers, suggest that selectively targeting extra chromosomes may offer a new route for treating cancer.

The study was published July 6 in the journal Science.

Human cells typically have 23 pairs of chromosomes; extra chromosomes are an anomaly 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,” said Jason Sheltzer, assistant professor of surgery at Yale School of Medicine and senior author of the study. “But we’ve known for over 100 years that nearly all cancers are aneuploid.”

However, it was unclear what role extra chromosomes played in cancer — for instance, whether they cause cancer or are caused by it.

The study was co-led by 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.

Using their newly developed approach — which they dubbed Restoring Disomy in Aneuploid cells using CRISPR Targeting, or ReDACT — the researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines. Specifically, they removed an aberrant third copy of the long portion — also known as the “q arm” — of chromosome 1, which is found in several types of cancer, is linked to disease progression, and occurs early in cancer development.

Based on this finding, the researchers proposed cancer cells may have an “aneuploidy addiction” — a name referencing earlier research that discovered that eliminating oncogenes, which can turn a cell into a cancer cell, disrupts cancers’ tumor-forming abilities. This finding led to a model of cancer growth called “oncogene addiction.”

Previous research has shown that a gene encoded on chromosome 1, known as UCK2, is required to activate certain drugs. In the new study, Sheltzer and his colleagues found that cells with an extra copy of chromosome 1 were more sensitive to those drugs than were cells with just two copies, because of the overexpression of UCK2.

More research needs to be done before this approach can be tested in a clinical trial. But Sheltzer aims to move this work into animal models, evaluate additional drugs and other aneuploidies, and team up with pharmaceutical companies to advance toward clinical trials.

Sources:

Vishruth Girish et al. Oncogene-like addiction to aneuploidy in human cancers. Science, 2023 DOI: 10.1126/science.adg452

Yale University. (2023, July 6). Eliminating extra chromosomes in cancer cells prevent tumor growth. ScienceDaily. Retrieved July 6, 2023 from www.sciencedaily.com/releases/2023/07/230706152349.htm

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