Eliminating extra chromosomes in cancer cells prevent tumor growth


Date:
July 6, 2023
Source:
Yale University
Summary:
Cancer cells with extra chromosomes depend on those chromosomes for
tumor growth, a new study reveals, and eliminating them prevents
the cells from forming tumors. The findings, said the researchers,
suggest that selectively targeting extra chromosomes may offer a
new route for treating cancer.


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FULL STORY ========================================================================== Cancer cells with extra chromosomes depend on those chromosomes for
tumor growth, a new Yale study reveals, and eliminating them prevents
the cells from forming tumors. The findings, said the researchers,
suggest that selectively targeting extra chromosomes may offer a new
route for treating cancer.

The study was published July 6 in the journal Science.

Human cells typically have 23 pairs of chromosomes; extra chromosomes
are an anomaly known as aneuploidy.

"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 Jason
Sheltzer, assistant professor of surgery at Yale School of Medicine and
senior author of the study. "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 -- for instance, 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, who is also a researcher
at Yale Cancer Center. "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." The study was co-led by former
lab members Vishruth Girish, now an M.D.-Ph.D.

student at Johns Hopkins School of Medicine, and Asad Lakhani, now a postdoctoral researcher at Cold Spring Harbor Laboratory.

Using their newly developed approach -- which they dubbed Restoring
Disomy in Aneuploid cells using CRISPR Targeting, or ReDACT -- the
researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian
cell lines. Specifically, they removed an aberrant third copy of the
long portion -- also known as the "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 tumors," said Sheltzer.

Based on this finding, the researchers proposed cancer cells may have
an "aneuploidy addiction" -- a name referencing earlier research that discovered that eliminating oncogenes, which can turn a cell into a cancer cell, disrupts cancers' tumor-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 nine 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."
* RELATED_TOPICS
o Health_&_Medicine
# Cancer # Brain_Tumor # Lung_Cancer # Skin_Cancer #
Colon_Cancer # Lymphoma # Prostate_Cancer # Leukemia
* RELATED_TERMS
o Human_genome o Meiosis o Turner_syndrome o Cancer o
Chemotherapy o Monoclonal_antibody_therapy o Prostate_cancer
o Brain_tumor

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========================================================================== Journal Reference:
1. Vishruth Girish et al. Oncogene-like addiction to aneuploidy
in human
cancers. Science, 2023 DOI: 10.1126/science.adg452 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230706152349.htm

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