Scientists track 'doubling' in origin of cancer cells



The findings, published on May 3 in Science, shed light on the dysregulation of the "cell cycle," the repetitive process by which cells create new cells from their genetic material, by a group of molecules and enzymes.

These discoveries offer insights into what happens when a group of molecules and enzymes trigger and regulate the "cell cycle," the repetitive process of making new cells from the cells' genetic material.

The results could be instrumental in developing treatments that target disruptions in the cell cycle, potentially halting the progression of cancers, as suggested by the researchers.

To proliferate, cells follow a precise sequence starting with duplicating their entire genome, followed by segregating the duplicated genomes, and finally dividing the replicated DNA equally into two "daughter" cells.

Human cells possess 23 pairs of chromosomes — half inherited from each parent, totaling 46, including the sex chromosomes X and Y. However, cancer cells are observed to undergo an intermediate state with double that number — 92 chromosomes. How this occurs has been a puzzle.

Sergi Regot, Ph.D., an associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, notes, "An enduring question among scientists in the cancer field is: How do cancer cell genomes get so bad?" He adds, "Our study challenges the fundamental knowledge of the cell cycle and makes us reevaluate our ideas about how the cycle is regulated."

Regot explains that stressed cells, after genome duplication, may enter a dormant or senescent state and mistakenly attempt to duplicate their genome again. Typically, these dormant cells are eliminated by the immune system after being identified as defective. However, as humans age, there are instances when the immune system fails to clear these cells. Left unchecked, these abnormal cells can duplicate their genome again, leading to chromosome shuffling during the subsequent division and the initiation of cancer growth.

In an attempt to unravel the molecular pathway that malfunctions in the cell cycle, Regot and graduate research assistant Connor McKenney, leading the Johns Hopkins team, focused on human cells lining breast ducts and lung tissue. These cells divide at a faster rate than others, providing more opportunities to observe the cell cycle.

Utilizing their expertise in imaging individual cells, Regot's lab identified the small percentage of cells that don't enter the dormant stage and continue to duplicate their genome.

In this new study, the team analyzed thousands of images of single cells during cell division. They developed glowing biosensors to label cyclin dependent kinases (CDKs), enzymes known for regulating the cell cycle.

They observed that various CDKs were activated at different stages of the cell cycle. When cells were exposed to environmental stressors such as drugs disrupting protein production, UV radiation, or sudden changes in water pressure around cells (osmotic stress), the activity of CDK 4 and CDK 6 decreased. Subsequently, five to six hours later, as cells prepared to divide, CDK 2 was also inhibited. At this point, the anaphase promoting complex (APC) was activated, typically occurring just before cell division (mitosis).

"In the stressed environment in the study, APC activation occurred before mitosis, contrary to its usual activation during mitosis," says Regot.

Approximately 90% of breast and lung cells enter a dormant state when exposed to environmental stressors. However, in their experiments, a small percentage of cells did not enter this dormant state.

The research team observed that about 5% to 10% of breast and lung cells resumed the cell cycle, duplicating their chromosomes again.

Through further experiments, the team linked increased activity of stress-activated protein kinases to the small percentage of cells bypassing the dormant stage and continuing to duplicate their genome.

Regot mentions ongoing clinical trials testing DNA-damaging agents with CDK-blocking drugs. He suggests, "It's possible that the combination of drugs may prompt some cancer cells to duplicate their genome twice, generating heterogeneity that ultimately confers drug resistance."

"There may be drugs that can block APC from activating before mitosis to prevent cancer cells from replicating their genome twice and halt tumor progression," Regot adds.

Other contributors to the study include Yovel Lendner, Adler Guerrero-Zuniga, Niladri Sinha, Benjamin Veresko, and Timothy Aikin from Johns Hopkins.

Funding for the study was provided by the National Institutes of Health National Institute of General Medical Sciences (T32-GM007445, 1R35GM133499) and National Cancer Institute (1R01CA279546), the National Science Foundation, and the American Cancer Society.

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