Mind-Blowing Revelation: Surprising Connection Discovered Between Chromosome Instability and Mysterious Epigenetic Changes!

The resulting study, which was published June 7 inNaturenot only opens up a fertile new area of ​​research in basic science biology, but also has implications for clinical care.

Chromosomal instability has to do with changes in the number of chromosomes carried by each cancer cell. Epigenetic alterations change which genes are turned on or off in a cell, but without changing the cell’s DNA code.

In his first year as a pharmacology doctoral student at Weill Cornell Medicine, Albert Agustinus rotated in the lab of Samuel Bakhoum, MD, PhD, whose research group at Memorial Sloan Kettering Cancer Center (MSK) studies how alterations in the number and structure of chromosomes drive cancer. Albert is also mentored by epigenetics expert Yael David, PhD, whose lab at MSK’s Sloan Kettering Institute takes a chemical biology approach to study the epigenetic regulation of transcription.

“He came up to me and said, ‘I’m interested in understanding the link between chromosome instability and epigenetic modifications,'” recalls Dr. Bakhoum. “And my response to him was, ‘Well, there’s no known link, but you’re welcome to find it!'”

And find one that did, expanding that initial research into a 32-author multi-institution collaboration published in a leading scientific journal. The study was jointly supervised by Bakhoum and David.

Agustinus recently recounted his first big “aha” moment on the project, for which he also received a PhRMA Foundation drug discovery grant.

He was sitting next to a lab partner and looking through the microscope. The cells he was looking at had tiny abnormal mininuclei scattered throughout the cell, a common consequence of chromosome instability. And they had been configured with fluorescent markers that would show the presence of epigenetic modifications.

“The micronuclei shone much brighter than the primary nucleus,” says Agustinus. “My lab partner told me, ‘I’ve never seen you smile so much before.'”

crazy chromosomes

Chromosomes are tightly packed strands of DNA that carry our genetic information. Normally, each of our cells has 46 chromosomes, half from one parent and half from the other. When a cell divides to make a new copy of itself, all those chromosomes are supposed to end up in the new cell, but in cancer the process can go terribly wrong.

“The big question my lab is trying to answer is how chromosomal instability drives cancer evolution, progression, metastasis, and drug resistance,” says Dr. Bakhoum. “It’s a hallmark of cancer, especially advanced cancers, where the normal process of cell division goes haywire. Instead of 46 chromosomes, you can have a cell with 69 chromosomes right next to a cell with 80 chromosomes.”

The prevailing wisdom in the field has been that cancer cells increase their chances of survival by shuffling their genetic material when they divide. This process increases the chances that some of the random changes will allow a cancer daughter cell to resist attacks by the immune system and medical interventions.

“However, this new research suggests that this is only part of the story,” says Bakhoum.

This is because you can have two cancer cells, each with the same number of extra copies of a given chromosome, but each have different genes that are turned on or off. This is due to epigenetic changes.

“Our work further suggests that mutations in the genes encoding epigenetic modifying enzymes are not actually needed for epigenetic abnormalities to occur. All that is needed is to have ongoing chromosome instability,” says Dr. Bakhoum. “It’s an unexpected but really important finding. And it also explains why we often find chromosome instability and epigenetic abnormalities in advanced drug-resistant cancers, even when there’s no evidence for the kinds of mutations we’d expect to create epigenetic havoc.” .”

Back and forth, or what do micronuclei have to do with cancer?

Tiny extra nuclei in cells, known as micronuclei, like the ones Agustinus saw through the microscope, are usually rare and are quickly removed by the cell’s natural repair mechanisms. When you have a lot of them, it’s a sign that something has gone terribly wrong, much like cancer does.

Like the primary nucleus of a cell, these micronuclei contain packets of genetic material. And when these micronuclei burst, which often happens, it causes even more problems, the research team found.

Dr. Bakhoum uses the metaphor of a traveler who takes on a foreign accent and brings him back home. The research demonstrated that sequestration of chromosomes in micronuclei disrupts the organization of chromatin, a complex of genetic components that are packaged into chromosomes during cell division.

This leads to ongoing epigenetic dysregulation, which continues long after a micronucleus reintegrates into a cell’s primary nucleus.

And the repeated formation and reincorporation of micronuclei over many cycles of cell division leads to the accumulation of epigenetic changes. These, in turn, lead to increasing differences between individual cancer cells.

The more variation between individual cancer cells within the same tumor, the more likely it is that some of the cells will be resistant to whatever treatment is thrown at them, allowing them to survive and continue their rampant growth.

Analysis of epigenetic changes

To understand and quantify the epigenetic changes that occur within cells, researchers use a series of sophisticated experiments to isolate micronuclei and examine the changes that occur in them compared to the cells’ primary nuclei. This allowed them to see patterns of histone modification: changes to the spools around which DNA winds, which, in turn, changes access to the underlying genes.

“This allowed us to ask some important questions, like do we really get the transcript of genes that are important in specific pathways?” says Dr David. “And the answer is yes.'”

They also compared intact versus ruptured micronuclei, revealing an even higher level of change in those that had burst.

“We also found that there were much more accessible promoter regions in the micronuclei than in the primary nuclei,” he adds. Promoter regions are DNA sequences near the beginning of a gene that help initiate transcription, a critical step in gene expression.

In a key experiment, the researchers forced a chromosome out into a micronucleus and then allowed it to reintegrate into the primary nucleus. They compared this adventurous chromosome to one that stayed put.

“Our model chromosome, which turned out to be the Y chromosome, showed substantial changes in its epigenetic landscape and the accessibility of its DNA,” says Dr. David. “This has important implications because of the significant impact that the journey from a chromosome to a micronucleus has on epigenetic changes in the primary nucleus, which we know play a role in tumor progression and evolution.”

The work, he adds, opens up new avenues of study.

“Now that we’ve shown that chromosome instability and epigenetic changes are closely related, we can dig deeper and ask questions about how and why,” says Dr. David.

Findings from another research team from Harvard University and the Dana-Farber Cancer Institute, and published in Nature at the same time it found additional evidence supporting the MSK team’s findings.

clinical implications

More than shedding light on the changes that occur within cancer cells, the research also holds promise for treating patients, the researchers say.

Epigenetic changes are a reversible form of gene regulation, and several classes of drugs have already been developed to work on them.

So for starters, chromosome instability and the presence of micronuclei could be used as biomarkers to help identify which patients are most likely to be helped by epigenetic-modifying drugs, says Dr. Bakhoum.

Furthermore, the findings may pave the way for new therapeutic approaches.

“There is the question of whether we should treat chromosomally unstable cells with these epigenetic modification therapies,” he says. “This research shows that epigenetic changes can occur without those mutations being present.”

In addition, the study also suggests that ongoing research on drugs to directly target chromosome instability could benefit from being combined with efforts to suppress epigenetic alterations, adds Dr. Bakhoum.

In the longer term, another potential avenue would be to explore ways to target micronuclei to prevent them from breaking, which the research showed was a big driver of epigenetic changes, says Dr. David.

“I think this is a great example of a fundamental, basic science research discovery that, over the next five years, will open up multiple exciting avenues for exploration and potential translation into the clinical setting,” he says.

Agustinus, whose curiosity kickstarted the entire project and who led the research effort, sums it up this way: “Chromosomal instability and epigenetic alterations help cancer achieve population diversity that gives them a better chance to survive and thrive. But armed with a new understanding of the relationship between these two phenomena, we should be better able to approach them therapeutically.”