Researchers from Stanford Medicine have discovered that cancer cells-to-be accumulate a series of specific genetic changes in a predictable and sequential way years before they are identifiable as pre-malignancies. Many of these changes affect pathways that control cell division, structure, and internal messaging — leaving the cells poised to go bad long before any visible signs or symptoms occur.
The study is the first to exhaustively observe the natural evolution of the earliest stages of human cancers, starting with cells that have a single cancer-priming mutation and culminating with a panel of descendants harboring a galaxy of genetic abnormalities.
Identifying the first steps associated with future cancer development could not only facilitate earlier-than-ever diagnosis — when a deadly outcome is but a twinkle in a rogue cell’s eye — but may also highlight novel interventions that could stop the disease in its tracks, the researchers say.
Curtis is the senior author of the research, which was published on May 31 in Nature. The lead authors of the study are former postdoctoral scholar Kasper Karlsson, Ph.D., and visiting graduate student Moritz Przybilla.
Cells of nefarious beginnings
The research builds on previous work in Curtis’s laboratory indicating that some colon cancer cells are seemingly born to be bad — they acquire the ability to metastasize long before the disease is detectable.
“Our studies of established tumors showed us that early genomic alterations seem to dictate what happens later, and that many of these changes seem to happen before tumor formation,” Curtis said. “We wanted to know what happens at the very earliest stages. How does a cancer cell evolve, and is this evolutionary path repeatable? If we start with a given set of conditions, will we get the same result in every case?”
The researchers studied tiny, three-dimensional clumps of human stomach cells called gastric organoids. The cells were obtained from patients undergoing gastric bypass surgery to treat obesity. At the beginning of the study, the researchers nudged the cells toward cancers by disabling the production of a key cancer-associated protein called p53 that regulates when and how often a cell divides. Mutations in p53 are known to be an early event in many human cancers, and they trigger the accumulation of additional genetic changes including mutations and copy number alterations — in which repetitive regions of the genome are lost or gained during cell division.
Then they waited.
Every two weeks, for two years, Karlsson cataloged the genetic changes occurring in the dividing cells. When Karlsson and Przybilla analyzed the data they found that, although changes occurred randomly, those that conferred greater fitness gave their host cells an evolutionary advantage over other cells in the organoid. As the cells continued to divide and the cycle of mutation and competition repeated over many iterations, the researchers saw some common themes.
Predictable pathways
“There are reproducible patterns,” Curtis said. “Certain regions of the genome are consistently lost very early after the initial inactivation of p53. This was repeatedly seen in cells from independent experiments with the same donor and across donors. This indicates that these changes are cell-intrinsic, that they are hardwired into tumor evolution. At the same time, these cells and organoids appear mostly normal under the microscope. They have not yet progressed to a cancer.”
The researchers found that these early changes usually occur in biological pathways that control when and how often a cell divides, that interfere with a cell’s intricate internal signaling network coordinating the thousands of steps necessary to keep it running smoothly, or that control cell structure and polarity — its ability to know what is “up” and “down” and to situate itself with respect to neighboring cells to form a functioning tissue.
The researchers saw similar patterns occur again and again in cells from different donors. Like water flowing downhill into dry creek beds, the cells traced tried-and-true paths, gaining momentum with each new genetic change. Several of these changes mirror mutations previously observed in stomach cancer and in Barrett’s esophagus, a pre-cancerous condition arising from cells that line the colon and stomach.
“These changes occur in a stereotyped manner that suggests constraints in the system,” Curtis said. “There’s a degree of predictability at the genomic level and even more so at the transcriptomic level — in the biological pathways that are affected — that gives insights into how these cancers arise.”
Curtis and her colleagues plan to repeat the study in different cell types and initiate events other than p53 mutation.
“We’re trying to understand exactly what malignant transformation is,” Curtis said. “What does it mean to catch these cells in the act, about to topple over the edge? We’d like to repeat this study with other tissue types and initiating mutations so we can understand the early genetic events that occur in different organs. And we’d like to study the interplay between the host and the environment. Do inflammatory factors play a role in promoting progression? We know that it matters that the cells in these organoids are communicating with each other, and that is important to understanding progression and treatment response.”
Reference: “Deterministic evolution and stringent selection during preneoplasia” by Kasper Karlsson, Moritz J. Przybilla, Eran Kotler, Aziz Khan, Hang Xu, Kremena Karagyozova, Alexandra Sockell, Wing H. Wong, Katherine Liu, Amanda Mah, Yuan-Hung Lo, Bingxin Lu, Kathleen E. Houlahan, Zhicheng Ma, Carlos J. Suarez, Chris P. Barnes, Calvin J. Kuo and Christina Curtis, 31 May 2023, Nature.
DOI: 10.1038/s41586-023-06102-8
Researchers from Karolinska Institutet, the University College London, and the Chan Zuckerberg Biohub also contributed to the study.
The research was supported by the National Institutes of Health (grants DP1-CA238296 and U01-CA217851) and the Swedish Research Council.
![](https://www.nanoappsmedical.com/wp-content/uploads/2017/05/spacer.jpg)
News
The Silent Battle Within: How Your Organs Choose Between Mom and Dad’s Genes
Research reveals that selective expression of maternal or paternal X chromosomes varies by organ, driven by cellular competition. A new study published today (July 26) in Nature Genetics by the Lymphoid Development Group at the MRC [...]
Study identifies genes increasing risk of severe COVID-19
Whether or not a person becomes seriously ill with COVID-19 depends, among other things, on genetic factors. With this in mind, researchers from the University Hospital Bonn (UKB) and the University of Bonn, in [...]
Small regions of the brain can take micro-naps while the rest of the brain is awake and vice versa
Sleep and wake: They're totally distinct states of being that define the boundaries of our daily lives. For years, scientists have measured the difference between these instinctual brain processes by observing brain waves, with [...]
Redefining Consciousness: Small Regions of the Brain Can Take Micro-Naps While the Rest of the Brain Is Awake
The study broadly reveals how fast brain waves, previously overlooked, establish fundamental patterns of sleep and wakefulness. Scientists have developed a new method to analyze sleep and wake states by detecting ultra-fast neuronal activity [...]
AI Reveals Health Secrets Through Facial Temperature Mapping
Researchers have found that different facial temperatures correlate with chronic illnesses like diabetes and high blood pressure, and these can be detected using AI with thermal cameras. They highlight the potential of this technology [...]
Breakthrough in aging research: Blocking IL-11 extends lifespan and improves health in mice
In a recent study published in the journal Nature, a team of researchers used murine models and various pharmacological and genetic approaches to examine whether pro-inflammatory signaling involving interleukin (IL)-11, which activates signaling molecules such [...]
Promise for a universal influenza vaccine: Scientists validate theory using 1918 flu virus
New research led by Oregon Health & Science University reveals a promising approach to developing a universal influenza vaccine—a so-called "one and done" vaccine that confers lifetime immunity against an evolving virus. The study, [...]
New Projects Aim To Pioneer the Future of Neuroscience
One study will investigate the alterations in brain activity at the cellular level caused by psilocybin, the psychoactive substance found in “magic mushrooms.” How do neurons respond to the effects of magic mushrooms? What [...]
Decoding the Decline: Scientific Insights Into Long COVID’s Retreat
Research indicates a significant reduction in long COVID risk, largely due to vaccination and the virus’s evolution. The study analyzes data from over 441,000 veterans, showing lower rates of long COVID among vaccinated individuals compared [...]
Silicon Transformed: A Breakthrough in Laser Nanofabrication
A new method enables precise nanofabrication inside silicon using spatial light modulation and laser pulses, creating advanced nanostructures for potential use in electronics and photonics. Silicon, the cornerstone of modern electronics, photovoltaics, and photonics, [...]
Caught in the actinium: New research could help design better cancer treatments
The element actinium was first discovered at the turn of the 20th century, but even now, nearly 125 years later, researchers still don't have a good grasp on the metal's chemistry. That's because actinium [...]
Innovative Light-Controlled Drugs Could Revolutionize Neuropathic Pain Treatment
A team of researchers from the Institute for Bioengineering of Catalonia (IBEC) has developed light-activated derivatives of the anti-epileptic drug carbamazepine to treat neuropathic pain. Light can be harnessed to target drugs to specific [...]
Green Gold: Turning E-Waste Into a Treasure Trove of Rare Earth Metals
Scientists are developing a process inspired by nature that efficiently recovers europium from old fluorescent lamps. The approach could lead to the long-awaited recycling of rare earth metals. A small molecule that naturally serves [...]
Cambridge Study: AI Chatbots Have an “Empathy Gap,” and It Could Be Dangerous
A new study suggests a framework for “Child Safe AI” in response to recent incidents showing that many children perceive chatbots as quasi-human and reliable. A study has indicated that AI chatbots often exhibit [...]
Nanoparticle-based delivery system could offer treatment for diabetics with rare insulin allergy
Up to 3% of people with diabetes have an allergic reaction to insulin. A team at Forschungszentrum Jülich has now studied a method that could be used to deliver the active substance into the [...]
Nanorobot kills cancer cells in mice with hidden weapon
Researchers at Karolinska Institutet in Sweden have developed nanorobots that kill cancer cells in mice. The robot's weapon is hidden in a nanostructure and is exposed only in the tumor microenvironment, sparing healthy cells. [...]