Scientists at Johns Hopkins Medicine have mapped a molecular pathway in human breast and lung cells that could lead to excessive genome duplication, a hallmark of cancer cells.
The findings, recently published in the journal Science, reveal what goes wrong when a group of molecules and enzymes trigger and regulate what's known as the "cell cycle," the repetitive process of making new cells out of the cells' genetic material.
The findings could be used to develop therapies that interrupt snags in the cell cycle, and have the potential to stop the growth of cancers, the researchers suggest.
To replicate, cells follow an orderly routine that begins with making a copy of their entire genome, followed by separating the genome copies, and finally, dividing the replicated DNA evenly into two "daughter" cells.
Human cells have 23 pairs of each chromosome — half from the mother and half from the father, including the sex chromosomes X and Y — or 46 total. However, cancer cells are known to go through an intermediate state that has double that number – 92 chromosomes. How this happens was a longstanding mystery.
"An enduring question among scientists in the cancer field is: How do cancer cell genomes get so bad?" says Sergi Regot, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine. "Our study challenges the fundamental knowledge of the cell cycle and makes us reevaluate our ideas about how the cycle is regulated."
Challenges in Cell Cycle Regulation
Regot says cells that are stressed after copying the genome can enter a dormant, or senescent stage, and mistakenly run the risk of copying their genome again.
Generally and eventually, these dormant cells are swept away by the immune system after they are "recognized" as faulty. However, there are times, especially as humans age, when the immune system can't clear the cells. Left alone to meander in the body, the abnormal cells can replicate their genome again, shuffle the chromosomes at the next division, and a growing cancer begins.
In an effort to pin down details of the molecular pathway that goes awry in the cell cycle, Regot and graduate 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 generally divide at a more rapid pace than other cells in the body, increasing the opportunities to visualize the cell cycle.
Watch this video of a cell going through the cell cycle stage of duplicating its genome twice without dividing. Bright points appear in the cell's nucleus indicating where DNA is being replicated. Credit: Sergi Regot lab, Johns Hopkins Medicine
Regot's lab specializes in imaging individual cells, making it especially suited to spot the very small percentage of cells that don't enter the dormant stage and continue replicating their genome.
For this new study, the team scrutinized thousands of images of single cells as they went through cell division. The researchers developed glowing biosensors to tag cellular enzymes called cyclin-dependent kinases (CDKs), known for their role in regulating the cell cycle.
They saw that a variety of CDKs activated at different times during the cell cycle. After the cells were exposed 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 cells), the researchers saw that CDK 4 and CDK 6 activity decreased.
Findings on Cell Cycle Disruptions
Then, five to six hours later, when the cells started preparations to divide, CDK 2 was also inhibited. At that point, a protein complex called the anaphase-promoting complex (APC) was activated during the phase just before the cell pulls apart and divides, a step called mitosis.
"In the stressed environment in the study, APC activation occurred before mitosis, when it's usually been known to activate only during mitosis," says Regot.
About 90% of breast and lung cells leave the cell cycle and enter a quiet state when exposed to any environmental stressors.
In their experimental cells, not all of the cells went quiet.
The research team watched as about 5% to 10% of the breast and lung cells returned to the cell cycle, dividing their chromosomes again.
Through another series of experiments, the team linked an increase in activity of so-called stress-activated protein kinases to the small percentage of cells that skirt the quiet stage and continue to double their genome.
Regot says there are ongoing clinical trials testing DNA-damaging agents with drugs that block CDK. "It's possible that the combination of drugs may spur some cancer cells to duplicate their genome twice and generate the heterogeneity that ultimately confers drug resistance," says Regot.
"There may be drugs that can block APC from activating before mitosis to prevent cancer cells from replicating their genome twice and prevent tumor stage progression," says Regot.
Reference: "CDK4/6 activity is required during G2 arrest to prevent stress-induced endoreplication" by Connor McKenney, Yovel Lendner, Adler Guerrero Zuniga, Niladri Sinha, Benjamin Veresko, Timothy J. Aikin and Sergi Regot, 3 May 2024, Science.
DOI: 10.1126/science.adi2421
Other researchers who contributed 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.
News
New study suggests a way to rejuvenate the immune system
Stimulating the liver to produce some of the signals of the thymus can reverse age-related declines in T-cell populations and enhance response to vaccination. As people age, their immune system function declines. T cell [...]
Nerve Damage Can Disrupt Immunity Across the Entire Body
A single nerve injury can quietly reshape the immune system across the entire body. Preclinical research from McGill University suggests that nerve injuries may lead to long-lasting changes in the immune system, and these [...]
Fake Science Is Growing Faster Than Legitimate Research, New Study Warns
New research reveals organized networks linking paper mills, intermediaries, and compromised academic journals Organized scientific fraud is becoming increasingly common, ranging from fabricated research to the buying and selling of authorship and citations, according [...]
Scientists Unlock a New Way to Hear the Brain’s Hidden Language
Scientists can finally hear the brain’s quietest messages—unlocking the hidden code behind how neurons think, decide, and remember. Scientists have created a new protein that can capture the incoming chemical signals received by brain [...]
Does being infected or vaccinated first influence COVID-19 immunity?
A new study analyzing the immune response to COVID-19 in a Catalan cohort of health workers sheds light on an important question: does it matter whether a person was first infected or first vaccinated? [...]
We May Never Know if AI Is Conscious, Says Cambridge Philosopher
As claims about conscious AI grow louder, a Cambridge philosopher argues that we lack the evidence to know whether machines can truly be conscious, let alone morally significant. A philosopher at the University of [...]
AI Helped Scientists Stop a Virus With One Tiny Change
Using AI, researchers identified one tiny molecular interaction that viruses need to infect cells. Disrupting it stopped the virus before infection could begin. Washington State University scientists have uncovered a method to interfere with a key [...]
Deadly Hospital Fungus May Finally Have a Weakness
A deadly, drug-resistant hospital fungus may finally have a weakness—and scientists think they’ve found it. Researchers have identified a genetic process that could open the door to new treatments for a dangerous fungal infection [...]
Fever-Proof Bird Flu Variant Could Fuel the Next Pandemic
Bird flu viruses present a significant risk to humans because they can continue replicating at temperatures higher than a typical fever. Fever is one of the body’s main tools for slowing or stopping viral [...]
What could the future of nanoscience look like?
Society has a lot to thank for nanoscience. From improved health monitoring to reducing the size of electronics, scientists’ ability to delve deeper and better understand chemistry at the nanoscale has opened up numerous [...]
Scientists Melt Cancer’s Hidden “Power Hubs” and Stop Tumor Growth
Researchers discovered that in a rare kidney cancer, RNA builds droplet-like hubs that act as growth control centers inside tumor cells. By engineering a molecular switch to dissolve these hubs, they were able to halt cancer [...]
Platelet-inspired nanoparticles could improve treatment of inflammatory diseases
Scientists have developed platelet-inspired nanoparticles that deliver anti-inflammatory drugs directly to brain-computer interface implants, doubling their effectiveness. Scientists have found a way to improve the performance of brain-computer interface (BCI) electrodes by delivering anti-inflammatory drugs directly [...]
After 150 years, a new chapter in cancer therapy is finally beginning
For decades, researchers have been looking for ways to destroy cancer cells in a targeted manner without further weakening the body. But for many patients whose immune system is severely impaired by chemotherapy or radiation, [...]
Older chemical libraries show promise for fighting resistant strains of COVID-19 virus
SARS‑CoV‑2, the virus that causes COVID-19, continues to mutate, with some newer strains becoming less responsive to current antiviral treatments like Paxlovid. Now, University of California San Diego scientists and an international team of [...]
Lower doses of immunotherapy for skin cancer give better results, study suggests
According to a new study, lower doses of approved immunotherapy for malignant melanoma can give better results against tumors, while reducing side effects. This is reported by researchers at Karolinska Institutet in the Journal of the National [...]
Researchers highlight five pathways through which microplastics can harm the brain
Microplastics could be fueling neurodegenerative diseases like Alzheimer's and Parkinson's, with a new study highlighting five ways microplastics can trigger inflammation and damage in the brain. More than 57 million people live with dementia, [...]
