Defeating Cancer Cells by Knocking out their Extra Chromosomes
Most cancer cells are aneuploid, having extra chromosomes, and they depend on those chromosomes for tumour growth, a new study in the journal Science reveals. Eliminating them prevents the cells from forming tumours, which suggests that selectively targeting extra chromosomes may lead to a new form of cancer treatment which could spare healthy tissue which has the typical 23 pairs.
“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 senior study author Jason Sheltzer, assistant professor of surgery at Yale School of Medicine. “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, such as whether they cause cancer or are caused by it.
“For a long time, we could observe aneuploidy but not manipulate it. We just didn’t have the right tools,” said Sheltzer. “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.”
Using their newly developed approach, which they dubbed Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT), the researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines. Specifically, they removed an aberrant third copy of the long portion, or ‘q arm’, of chromosome 1, which is found in several types of cancer, is linked to disease progression, and occurs early in 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 tumours,” said Sheltzer.
Based on this finding, the researchers proposed cancer cells may have an ‘aneuploidy addiction’ – a discovery that eliminating oncogenes, which can turn a cell into a cancer cell, disrupts cancers’ tumour-forming abilities. This finding led to a model of cancer growth called ‘oncogene addiction’.
When investigating how an extra copy of chromosome 1q might promote cancer, the researchers found that multiple genes stimulated cancer cell growth when they were overrepresented – because they were encoded on three chromosomes instead of the typical two.
This overexpression of certain genes also pointed the researchers to a vulnerability that might be exploited to target cancers with aneuploidy.
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.
Further, they observed that this sensitivity meant that the drugs could redirect cellular evolution away from aneuploidy, allowing for a cell population with normal chromosome numbers and, therefore, less potential to become cancerous. When researchers created a mixture with 20% aneuploid cells and 80% normal cells, aneuploid cells took over: after 9 days, they made up 75% of the mixture. But when the researchers exposed the 20% aneuploid mixture to one of the UCK2-dependent drugs, the aneuploid cells comprised just 4% of the mix nine days later.
“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.”
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.
“We’re very interested in clinical translation,” said Sheltzer. “So we’re thinking about how to expand our discoveries in a therapeutic direction.”
Source: Yale University
