Working with human breast and lung cells, scientists at Johns Hopkins Medicine Hospital (USA) claim to have mapped out a molecular pathway that can lead cells down the dangerous path of duplicating their genome too many times, a hallmark of cancer cells.
The findings, published in the journal ‘Science’, reveal what goes wrong when a group of molecules and enzymes trigger and regulate what is known as the cell cycle, the repetitive process of creating new cells from their genetic material.
The researchers suggest that these findings could be used to develop therapies that stop cell cycle arrests and could stop the growth of cancers.
To replicate, cells follow an orderly routine that begins with making one copy of their entire genome, followed by separating copies of the genome, and finally evenly dividing the replicated DNA into two daughter cells.
Human cells have 23 pairs of each chromosome – half from the mother and half from the father, including the X and Y sex chromosomes – or 46 in total, but cancer cells are known to go through an intermediate state that has double that number: 92 chromosomes. How this happens was a mystery.
“A persistent question among scientists in the oncology field is: How do the genomes of cancer cells become so damaged?” said Sergi Regot, associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine.
“Our study challenges fundamental knowledge of the cell cycle and makes us reevaluate our ideas about how the cycle is regulated,” added Regot.
In this sense, the researcher states that cells that suffer stress after copying the genome can enter a latent, or senescent, phase and mistakenly run the risk of copying their genome again.
Typically, over time, these inactive cells are swept away by the immune system after recognizing them as defective. However, there are times, especially as humans age, when the immune system cannot eliminate the cells. Left alone in the body, the abnormal cells can replicate their genome again, shuffle the chromosomes in the next division, and a growing cancer begins.
BREAST AND LUNG CELLS
In an effort to pin down the details of the molecular pathway that bypasses the cell cycle, Regot and research assistant Connor McKenney, who led the Johns Hopkins team, focused on human cells that line breast ducts and lung tissue. . The reason: These cells tend to divide at a faster rate than other cells in the body, which increases the chances of visualizing the cell cycle.
Regot’s lab specializes in imaging single cells, making it especially suited to detecting the very small percentage of cells that do not enter the dormant phase and continue to replicate their genome.
For this new study, the team analyzed thousands of images of individual cells as they went through cell division. The researchers developed brilliant biosensors to label cellular enzymes called cyclin-dependent kinases (CDKs), known for their role in regulating the cell cycle.
They observed that several CDKs were activated at different times in the cell cycle. After exposing the cells to an environmental stressor, such as a drug that disrupts protein production, UV radiation, or so-called osmotic stress (a sudden change in water pressure around the cells), the researchers observed that the activity of CDK 4 and CDK 6 decreased.
Then, five to six hours later, as the cells began to prepare to divide, CDK 2 was also inhibited. At that time, a protein complex called the anaphase-promoting complex (APC) was activated during the phase just before the cell separates and divides, a step called mitosis.
“In the stressed environment of the study, APC activation occurred before mitosis, when it is normally known to only be activated during mitosis,” says Regot.
About 90 percent of breast and lung cells exit the cell cycle and enter a resting state when exposed to any environmental stressor.
In their experimental cells, not all the cells stayed still. The research team watched as 5 to 10 percent of breast and lung cells returned to the cell cycle, dividing their chromosomes again.
Through another series of experiments, the team linked an increase in the activity of so-called stress-activated protein kinases to the small percentage of cells that bypass the quiescent phase and continue duplicating their genome.
Regot says there are ongoing clinical trials testing DNA-damaging agents with drugs that block CDKs. “It is possible that the combination of drugs drives some cancer cells to duplicate their genome and generate the heterogeneity that ultimately confers drug resistance,” says Regot.
“There may be drugs that can block the activation of APC before mitosis to prevent cancer cells from replicating their genome twice and prevent progression of the tumor phase,” Regot concluded.
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