Recent research from Yale University has shown that additional chromosomes in cancer cells are essential for tumor growth. Removal of these extra chromosomes suppresses tumor formation. The researchers say their findings indicate that selectively targeting extra chromosomes may offer a new route to cancer treatment.
This study was recently published in the journal science.
Human cells normally have 23 pairs of chromosomes. An extra chromosome is an abnormality known as an aneuploidy.
“If you look at normal skin or normal lung tissue, for example, 99.9% of the cells have the right number of chromosomes,” said Jason Scherzer, assistant professor of surgery at Yale University School of Medicine and senior author of the study. says. “But we have known for over 100 years that almost all cancers are aneuploid.”
However, it was unclear what role the extra chromosome plays in cancer, for example, whether it causes or is caused by cancer.
“For a long time, we could observe aneuploidy, but we couldn’t manipulate it. We didn’t have the right tools,” says the Yale Cancer Center study. Mr. Scherzer, who is also a person, said. “But in this study, we used the genetic engineering technique CRISPR to develop a new approach to removing whole chromosomes from cancer cells. This is an important technological advance.” Being able to manipulate them will lead to a better understanding of how chromosomes work. “
The study was co-led by former lab member and now MD Vishruth Girish. Asad Lakhani, a Johns Hopkins University School of Medicine student and current postdoctoral fellow at Cold Spring Harbor Laboratory.
The researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines using a newly developed approach they termed (CRISPR targeting, or repair of aneuploid cells using ReDACT). did. Specifically, they removed the abnormal third copy of the long segment of chromosome 1 (also called the “q arm”). This part is found in several types of cancer, is associated with disease progression, and occurs in the early stages of cancer development.
“When we removed the aneuploidy from the genomes of these cancer cells, we compromised their malignancy and eliminated their ability to form tumors,” Scherzer said.
Based on this finding, the researchers proposed that cancer cells may have an “aneuploid dependence.” The name comes from previous research that found that removing oncogenes that can turn cells into cancer cells inhibits cancer’s ability to form tumors. This discovery led to a model of cancer growth called ‘oncogene addiction’.
Researchers investigated how extra copies of chromosome 1q promote cancer and found that multiple gene excesses stimulated cancer cell proliferation. This was because these genes were encoded on her three chromosomes instead of her usual two.
Overexpression of this particular gene also pointed the researchers to a vulnerability that could be exploited to target aneuploid cancers.
Previous studies have shown that there is a gene encoded on chromosome 1 known as . UCK2, is required to activate certain drugs. In a new study, Scherzer and colleagues found that cells with an extra copy of chromosome 1 were more sensitive to these drugs than cells with only two copies. UCK2.
In addition, this susceptibility, they say, could cause the drug to keep cells evolving away from aneuploidy, allowing for cell populations with normal chromosome numbers and thus less chance of becoming cancerous. Observed. When the researchers created a mixture containing 20% aneuploid cells and 80% normal cells, the aneuploid cells took over, making up his 75% of the mixture after nine days. However, when the researchers exposed a 20% aneuploid mixture to either UCK2For drugs of abuse, aneuploid cells accounted for only 4% of the mixture after 9 days.
“This shows that aneuploidy can potentially serve as a therapeutic target in cancer,” Scherzer said. “Almost all cancers are aneuploid, so if there were some way to selectively target these aneuploid cells, it would theoretically have minimal impact on normal, non-cancerous tissue. It could be a good way to target cancer while reducing
More research needs to be done before this approach can be tested in clinical trials. But Scherzer hopes to transfer the study to animal models, evaluate additional drugs and other aneuploidies, and work with pharmaceutical companies to advance the study to clinical trials.
“We are very interested in clinical translation,” Scherzer said. “So we’re looking at ways to extend our discoveries in the direction of therapy.”
Reference: “Oncogene-Like Addiction to Aneuploidy in Human Cancer” Vishruth Girish, Asad A. Lakhani, Sarah L. Thompson, Christine M. Scaduto, Leanne M. Brown, Ryan A. Hagenson, Erin L. Sausville , Brianna E. Mendelsohn, Pranav K. Kandykuppa, Devon A. Lukow, Monet Lu Yuan, Eric C. Stevens, Sophia N. Lee, Kraske M. Shukken, Saron M. Akar , Anand Vasudevan, Charles Zou, Barbora Sarovska, Wenshwe Lee, Joan C. Smith, Alison M. Taylor, Robert A. Martiensen, Yansheng Liu, Lupine Sun, Jason M. Scherzer, July 6, 2023, science.
DOI: 10.1126/science.adg4521