WASHINGTON — Some cancers are addicted to having extra chromosomes, a study in mice suggests.
Cells usually have just two copies of each chromosome — one inherited from mom and one from dad. But about 90 percent of cancer cells have additional chromosomes, a condition called aneuploidy.
Certain types of cancer cells often carry a third copy of a particular chromosome or part of a chromosome. For instance, more than half of colorectal tumors have a surplus chromosome 13, and more than 40 percent carry an extra chromosome 7 or the long arm of chromosome 8 (SN: 5/31/18). Stocking spare copies of chromosomes has been associated with poorer outcomes for patients compared with patients whose cancers have the usual two copies.
It turns out that those extra doses of genetic material are necessary for the cancer cells to keep growing, cancer geneticist Jason Sheltzer reported December 11 at the joint annual meeting of the American Society for Cell Biology and the European Molecular Biology Organization. Put another way, cancer tumors are addicted to the bonus chromosomes, he says.
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The idea of “addicted” cancer cells isn’t completely new. Scientists have known for decades that cancer cells can be addicted to altered versions of certain genes, meaning that those genes are required for the continued cancerous growth of the cells.
As for chromosomes, researchers have speculated for more than a century that some cancers have particular chromosome surpluses that spur growth. But the ability to specifically delete specific chromosomes to test the idea is new, says Beth Weaver, a cancer cell biologist at the University of Wisconsin–Madison, who was not involved in the work.
In the new research, Sheltzer, of Cold Spring Harbor Laboratory in New York, developed a method for purging extra copies of whole chromosomes or parts of chromosomes from cells. A type of ovarian cancer cell called A2780 carries an extra copy of the long arm of chromosome 1, known as 1q. Sheltzer used his manipulation technique to remove the extra copy of 1q from the cancer cells, then compared how well the original and 1q-deprived cancer cells grew in lab dishes and when transplanted into mice.
Cells with the surplus chromosome arm formed many large colonies in dishes and grew into tumors in mice. But cells that lost 1q “barely grew at all,” Sheltzer said. “They’ve almost entirely lost their ability to exhibit malignant growth.” What’s more, cells from which the extra arm had been removed later somehow regained another copy, restoring the cells’ growth. “These cells for some reason really, really, really want to have three copies of this chromosome arm,” he said.
That result is persuasive, says cancer cell biologist Adrian Saurin of the University of Dundee in Scotland. “That’s a real sign of addiction, if you take it away and they manage to get it back again,” he says.
The idea that cancer cells can be addicted to genes forms the basis for many targeted cancer therapies, which interfere with the action of genes driving the cancer. Chromosomes, however, contain thousands of genes, so narrowing down which of those many genes or combination of genes is the source of addiction is much more complicated.
But finding out which genes turn cancer cells into addicts is necessary if researchers are ever going to develop treatments to negate the effect of bonus chromosomes, Saurin says. “We probably need to understand a lot more of the biology [of cancer cells] before [the new research] becomes clinically useful,” he says. “But I could see it in the future.”
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Sheltzer took a step toward pinpointing why 1q has ovarian cancer cells hooked. The chromosome arm contains more than 1,000 genes, but Sheltzer found a likely culprit in the gene MDM4. That gene produces a protein that inhibits activity of p53, a protein that helps prevent cancer. With more MDM4 protein around, p53’s tumor-suppressing activity is diminished, allowing cancer cells to grow unchecked, Sheltzer reasoned.
To test that idea, he used the gene editor CRISPR/Cas9 to remove the MDM4 gene from the surplus 1q (SN: 8/14/19). Cells lacking the third copy of MDM4 formed fewer colonies in lab dishes than cells with three copies, he found. But further experiments showed that gene isn’t the only one spurring the growth.
For now, the work is still preliminary, and Sheltzer hopes to do similar experiments with other types of cancers to determine whether aneuploidy addiction is common to all cancers.