Cancer cells with extra chromosomes need them to grow tumors

According to a recent study, tumor growth in cancer cells can be hindered by eliminating extra chromosomes. Researchers have found that these additional chromosomes play a vital role in supporting the growth of tumors. Targeting and removing these extra chromosomes can prevent the formation of tumors. This groundbreaking discovery suggests a promising new approach to treating cancer by selectively eliminating these abnormal chromosomes.

Extra chromosomes in cancer cells are crucial for tumor growth. However, a recent study by Yale University has shown that removing them prevents tumor formation. The researchers suggest selectively targeting these additional chromosomes could provide a novel approach to cancer treatment. The study was published in Science on July 6. It highlighted the abnormality of aneuploidy, where human cells typically possess 23 pairs of chromosomes.

Jason Sheltzer, assistant professor of surgery at Yale School of Medicine and senior author of the study, said, “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.”

The role of extra chromosomes in cancer has been a longstanding mystery, with uncertainty regarding whether they cause cancer or are a consequence of it. However, a recent study led by Yale University sheds light on this question. Using the gene-engineering technique CRISPR, the researchers developed a groundbreaking approach to eliminate entire chromosomes from cancer cells.

This significant technical advancement allowed them to manipulate aneuploid chromosomes, leading to a greater understanding of their function. The study was co-led by Vishruth Girish, an M.D.-Ph.D. student at Johns Hopkins School of Medicine, and Asad Lakhani, a Cold Spring Harbor Laboratory postdoctoral researcher.

Researchers successfully targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines using their innovative approach, called ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting). They specifically focused on removing an abnormal third copy of the extended portion (q arm) of chromosome 1, which is frequently observed in various cancer types, associated with disease progression, and occurs early in cancer development. Remarkably, eliminating aneuploidy from the genomes of these cancer cells using ReDACT significantly compromised their malignant potential, losing their ability to form tumors.

Based on these findings, the researchers put forward the concept of “aneuploidy addiction” in cancer cells, drawing a parallel to the earlier discovery of “oncogene addiction,” demonstrating that eliminating oncogenes disrupts the tumor-forming abilities of cancers.

Researchers investigating the role of an extra copy of chromosome 1q in promoting cancer found that overrepresented genes on three chromosomes instead of the typical two stimulated cancer cell growth. This overexpression revealed a vulnerability that could be targeted in cancers with aneuploidy.

The study also showed that cells with an extra copy of chromosome 1 were more sensitive to certain drugs due to overexpression of the UCK2 gene, encoded on chromosome 1 and required for drug activation.

This drug sensitivity redirected cellular evolution away from aneuploidy, resulting in a cell population with normal chromosome numbers and reduced cancer development potential. In an experimental mixture of 20% aneuploid cells and 80% normal cells, exposure to a UCK2-dependent drug reduced the percentage of aneuploid cells from 75% to 4% 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.” Although further research is needed before this approach can be tested in clinical trials, Sheltzer plans to progress the work into animal models, explore additional drugs and aneuploidies, and collaborate with pharmaceutical companies to advance toward clinical trials. The aim is to expand these discoveries in a therapeutic direction focusing on clinical translation.

Journal Reference:

Vishruth Girish et al., Oncogene-like addiction to aneuploidy in human cancers.Science.DOI:10.1126/science.adg4521.

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