CRISPR: Eliminate redundant chromosomes in cancer cells and prevent tumor growth

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CRISPR: Eliminate redundant chromosomes in cancer cells and prevent tumor growth

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CRISPR: Eliminate redundant chromosomes in cancer cells and prevent tumor growth.

As we all know, our human cells usually have 23 pairs of chromosomes, but cells may also have extra chromosomes, which is called aneuploidy (aneuploidy) .

If we look at normal tissue, 99.9% of the cells have a normal number of chromosomes, however, more than 100 years ago, scientists discovered that almost all cancers are aneuploidy, but it has been unclear how this phenomenon is in cancer Exactly what role it plays has been debated whether aneuploidy causes cancer or whether cancer causes aneuploidy.

Cancer cells carrying extra chromosomes depend on them to grow, and eliminating these extra chromosomes prevents tumors from forming, a new Yale study shows.

This finding also suggests that selective targeting of extra chromosomes may provide new avenues for cancer therapy.

The research titled: Oncogene-like addiction to aneuploidy in human cancers was published in the journal Science on July 6, 2023 [2] .

For a long time, we were able to observe aneuploidy but not manipulate it, largely because the right tools were not available.

But in this latest study, the research team used CRISPR gene editing technology to eliminate entire chromosomes in cancer cells, an important technological advance that manipulating aneuploid chromosomes in this way will allow us to better understand their function.

The research has developed a method called Re storing Disomy in A neuploid cells using C RISPR T targeting ( referred to as ReDACT ) , which uses CRISPR gene editing to target the removal of aneuploid chromosomes and restore the chromosomal diploidy of cells.

The research team targeted aneuploidy in melanoma, gastric and ovarian cancer cell lines. Specifically, they used ReDACT technology to remove the third abnormal copy of the long arm of chromosome 1 (1q) , an aneuploidy found in several cancer types that is associated with disease progression and occurs early in cancer development.

The results showed that when aneuploidy was eliminated from these cancer cell lines, the malignant potential of the cancer cells was impaired and they lost their ability to form tumors.

Based on this finding, the research team proposed that cancer cells may have aneuploidy addiction , a name that refers to oncogene addiction .

The research team further explored why an extra copy of the long arm of chromosome 1 (1q) promotes cancer.

They found that this extra copy of the long arm of chromosome 1 led to the overexpression of multiple genes (from two copies to three copies). copies) , thereby stimulating the growth of cancer cells.

Overexpression of this specific gene also points to a weakness that could potentially be exploited to target aneuploid cancers.

Previous studies have shown that the UCK2 gene, encoded on chromosome 1, is required to activate certain cancer treatment drugs such as RX-3117, 3- Deazauridine . In this latest study, the research team found that cells with multiple copies of chromosome 1 were more sensitive to these drugs than normal cells due to the overexpression of the UCK2 gene.

The research team further observed that this change in drug sensitivity can change the direction of cell evolution, make the cell population out of aneuploidy, and reduce the possibility of cancer.

They mixed 20 percent aneuploid cells with 80 percent normal cells, and after 9 days, the aneuploid cells prevailed, accounting for 75 percent of the total cell population. However, after mixing 20% ​​of aneuploid cells with 80% of normal cells and giving UCK2-dependent drugs, after 9 days, only 4% of aneuploid cells remained .

These results suggest that aneuploidy can be used as a potential therapeutic target in cancer. Almost all cancers are aneuploid.

If these aneuploid cells can be selectively targeted, it may be possible in the treatment of normal, non-cancerous cells. Kills cancer cells with minimal tissue impact.

Professor Jason Sheltzer , the corresponding author of the paper , said that we are very interested in clinical translation and are considering how to extend this discovery to the therapeutic field.

Of course, this requires further research. The lab now aims to validate the discovery in animal models and advance clinical trials in collaboration with pharmaceutical companies.

It is worth mentioning that on June 28, 2023, researchers from the Broad Institute published a research paper entitled: Cancer aneuploidies are shaped primarily by effects on tumor fitness  in the journal  Nature  .

The study, which developed a computational method called BISCUT , determined that loss of chromosomal aneuploidy drives cancer development, rather than being a concomitant event during cancer development.

Taken together, these two recently published studies solve a century-old puzzle that has existed for more than 100 years. More importantly, these discoveries bring new potential treatments and targets for many cancers.

Paper link :

1. https://www.science.org/doi/10.1126/science.adg4521

2.  https://www.nature.com/articles/s41586-023-06266-3

CRISPR: Eliminate redundant chromosomes in cancer cells and prevent tumor growth

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