CRISPR solves mystery of why cancer cells have extra chromosomes

　　Scientists have long known that cancer cells often have extra chromosomes, but what exactly is this extra genetic material doing?

　　New research from a team at Yale University finally provides the answer. There are typically 23 pairs of chromosomes in human cells. Extra chromosomes are called aneuploidy. The study, published July 6 in the journal Science, shows that these extra chromosomes can be used to fuel tumor growth and serve as a new way to treat cancer.

　　The study was co-led by Vishruth Girish, a doctoral student at the Johns Hopkins University School of Medicine, and Asad Lakhani, a postdoctoral researcher at Cold Spring Harbor Laboratory, both of whom worked in the laboratory of senior academic author Jason Sheltzer, Ph.D.

　　"If you look at normal skin or normal lung tissue, for example, 99.9 percent of the cells have the correct number of chromosomes," said Sheltzer, assistant professor of surgery at Yale School of Medicine. "But we've known for more than 100 years that almost all cancers have the correct number of chromosomes." All are aneuploid.”

　　Researchers are not sure whether the extra chromosome caused the cancer in the first place or whether it mutated because of the cancer. Previously, they had been able to see extra chromosomes, but had no way to change them—the advent of CRISPR gave them a breakthrough.

　　Sheltzer's team used gene-editing technology to come up with a new way to eliminate entire chromosomes in cancer cells and observe them. They call the technique Restoring Chromosome Excision in Aneuploid Cells Using CRISPR Targeting Technology, or ReDACT.

　　The researchers looked at cell lines from melanoma, gastric and ovarian cancers that removed extra copies of chromosome 1, which is associated with disease progression and occurs early in cancer development.

　　When the extra chromosomes are removed, the cancer cells lose their ability to form tumors, Sheltzer said. Researchers suspect cancer cells may have an "aneuploidy addiction." They also found that when the ratio of multiple genes is too high, it stimulates cancer cell growth.

　　So how can drugmakers use this to develop new treatments? Researchers suspect that overexpression of certain genes is a vulnerability in tumors. Previous research has shown that a gene on chromosome 1 is required to activate certain drugs.

　　The team found that if there are extra copies of this chromosome, the cancer becomes more sensitive to the drug. Given this sensitivity, the drug can even promote the growth of cell lines without extra chromosomes—meaning cells are less likely to become cancerous and spread.

　　"What this tells us is that aneuploid cells have the potential to be therapeutic targets in cancer," Sheltzer said. "Almost all cancers are aneuploid, so if you had a way to selectively target those aneuploid cells, then Theoretically, this could be a good way to target cancer with minimal impact on normal, non-cancerous tissue."

　　The next steps, Sheltzer said, are to start studies in animal models, consider which drugs might best target the extra chromosomes, and perhaps work with pharmaceutical companies to advance this approach into clinical trials.

References:

1. CRISPR solves mystery of why cancer cells have extra chromosomes. https://www.fiercebiotech.com/research/crispr-helps-solve-100-year-mystery-why-cancer-cells-have-extra-chromosomes