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Century-old cancer chromosome puzzle solved by CRISPR 



Biologists using modern gene-editing tools have discovered that the intuition of scientists from more than 100 years ago was right: cells with unusual numbers of chromosomes are drivers of cancer.

The study, by researchers from Yale School of Medicine and published in the journal Science, renews scientific attention on an old-fashioned idea, one that could point toward new ways to target cancer cells with drugs.

The Washington Post reports that scientists first noticed the phenomenon when examining cancer cells under a microscope in the early 1900s. They observed that, as cancer cells multiplied, some ended up with too many chromosomes, structures that we now know carry genes. Others wound up with too few.

The jarring observation led a German embryologist to propose that aberrant numbers of chromosomes weren't just a hallmark of cancer – perhaps they were causing it. The idea largely fell out of favour as scientists began to discover dozens of individual genes that caused cancer and developed drugs to target them.

But cancer cells’ chromosomal disorder remained an oddity, a common thread in 90% of cancers. Everyone knew it was there; no one was sure why or what it meant.

“It was overlooked, to some extent, and the reason for that is it was just really challenging to study,” said Uri Ben-David, an associate professor of human molecular genetics and biochemistry at Tel Aviv University who was not involved in the new study. “For many decades, it was kind of ignored – like an elephant in the cancer research room.”

In the new study, scientists have figured out how to tackle the mystery using a clever CRISPR hack. Their work showed that without extra chromosomes, certain cancer cells can no longer seed tumours in animals.

Humans have 23 pairs of chromosomes. Normally when cells divide, chromosomes make copies of themselves and then separate tidily and symmetrically into new cells. But in cancer, this choreography goes helter-skelter, and cells end up with abnormal numbers of chromosomes.

For decades, a classic conundrum in science stymied research into this phenomenon: Were the aberrations the cause of cancer, or simply a sign that things had already gone haywire in the cell? Back then, chromosomes weren’t easy to add or remove, so scientists searching for answers had to rely largely on intriguing correlations.

One study exposed melanoma cells to a chemical that further disrupted their chromosomes; those cells were faster to develop resistance to a targeted drug, suggesting that chromosomal abnormalities might play a role in cancer’s ability to thwart drugs.

Another found that the more chromosomally unstable a patient’s tumour cells were, the more likely their cancer was aggressive and their prognosis poor.

Again, the question of cause and effect loomed: could it be that chromosomal disruption was playing a role in those cancers, or was it only a downstream effect?

With the invention of CRISPR gene editing technology a decade ago, scientists gained the ability to add, delete or tweak genes. But deleting a whole chromosome is a different matter.

To do full-scale chromosome engineering, Jason Sheltzer, a cancer biologist at Yale School of Medicine, and his team had to deploy a CRISPR hack. First, they inserted a gene from the herpes virus on to a cancer cell’s extra chromosomes. Initially, they chose chromosome 1q, which is one of the first to gain or lose extra copies during the development of breast cancer.

They then used a herpes treatment, ganciclovir, to target the modified chromosomes. The technique killed the cells with extra copies, leaving behind cancer cells with normal numbers of chromosomes.

When they tried to grow tumours from this subpopulation of cancer cells, they found that the cells were no longer capable of seeding tumours in a petri dish or in live mice.

To Sheltzer, this was clear evidence that extra chromosomes weren’t just an effect, but a driver of the disease.

“It has a central role,” he said.

New ways to attack cancer


For now, the technique is a tool, not a therapy. It’s not yet feasible to think about restoring normal numbers of chromosomes in cancer cells as a way of staving off the disease.

But it may point toward a different way to target cancer in the future. Genetic understanding of cancer has led to therapies that target specific mutations that drive its progression. But cancer is a wily foe and often develops resistance to any one therapeutic approach.

The recognition that extra chromosomes are crucial to driving cancer means researchers can attack from a new direction: finding and killing cells that contain extra chromosomes.

Because chromosomes contain hundreds or thousands of genes, such an approach could expand the number of targets. Even if the cancer eventually became “resistant” to such a drug by losing its extra chromosomes, the study suggests that doing so might also squash its cancer-causing ability.

In essence, the extra chromosome becomes a new therapeutic vulnerability, Sheltzer said.

Because the cells have all this other genetic material, such cells may “become sensitive to drugs targeting a gene, even if it has nothing to do with cancer”.

Study details

Oncogene-Like Addiction To Aneuploidy In Human Cancers

Vishruth Girish,  Asad Lakhani, Sarah Thompson, Christine Scaduto, Jason Sheltzer.

Published in Science on 6 July 2023

Abstract

Most cancers exhibit aneuploidy, but its functional significance in tumour development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harbouring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these “aneuploidy addictions” could be targeted as a therapeutic strategy.

 

Science article – Oncogene-Like Addiction To Aneuploidy In Human Cancers (Open access)

 

The Washington Post article – Gene editing helped crack a 100-year-old mystery about cancer (Restricted access)

 

See more from MedicalBrief archives:

 

CRISPR technology makes significant headway in cancer treatment

 

CRISPR targets and kills blood cancer cells

 

Molecule makes cancer cells self-destruct

 

 

 

 

 

 

 

 

 

 

 

 

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