The study is the first to comprehensively look at the natural history of early-stage human cancers, starting with cells that carry a single cancer-causing mutation and culminating in a panel of offspring harboring a galaxy of genetic abnormalities.

Identifying the early steps associated with the future development of cancer could not only facilitate diagnosis earlier than ever, when a deadly outcome is just a twinkle in the eye of a rogue cell, but may also highlight novel interventions that could stop the disease, say the researchers.

“Ideally, we would find ways to intercept this progression before the cells become truly cancerous,” said Christina Curtis, PhD, professor of medicine, genetics, and biomedical data science. “Can we identify a minimal constellation of genetic alterations that mean the cell will progress? And if so, can we intervene? The amazing reproducibility in the genetic changes we see from multiple donors suggests that it is possible.”

Curtis is the lead author of the research, which was published May 31 in Nature. The study’s lead authors are former postdoctoral fellow Kasper Karlsson, PhD, and visiting graduate student Moritz Przybilla.

Cells of Ominous Beginnings

The research builds on previous work in Curtis’s lab indicating that some colon cancer cells are apparently born bad: They gain the ability to metastasize long before disease is detectable.

“Our studies of established tumors showed us that early genomic alterations appear to dictate what happens later, and that many of these changes appear to occur before tumor formation,” Curtis said. “We wanted to know what happens at the earliest stages. How does a cancer cell evolve? Is this evolutionary path repeatable? If we start with a certain set of conditions, will we get the same result every time?”

The researchers studied small three-dimensional groups of cells in the human stomach called gastric organoids. The cells were obtained from patients who underwent gastric bypass surgery to treat obesity. At the start of the study, the researchers pushed cells toward cancer by turning off 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 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 that occurred in dividing cells. When Karlsson and Przybilla analyzed the data, they found that although the 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 soon after the initial inactivation of p53. This was repeatedly observed in cells from independent experiments with the same donor and between donors. This indicates that these changes are intrinsic to the cell, that they are integrated into the evolution of the tumor. At the same time, these cells and organoids appear mostly normal under the microscope. They have not yet progressed to cancer.”

The researchers found that these early changes typically occur in biological pathways that control when and how often a cell divides, interfere with a cell’s intricate internal signaling network that coordinates the thousands of steps required for it to function smoothly, or control the structure and polarity of the cell – its ability to know what is “up” and “down” and to position itself relative to neighboring cells to form a functional tissue.

The researchers observed that similar patterns occurred over and over again in cells from different donors. Like water flowing downhill into dry creek beds, cells forged tried-and-true paths, gaining momentum with each new genetic change. Several of these changes reflect mutations previously seen in stomach cancer and Barrett’s esophagus, a precancerous condition that arises from cells lining the colon and stomach.

“These changes occur in a stereotyped way that suggests constraints in the system,” Curtis said. “There is a degree of predictability at the genomic level and even more so at the transcriptomic level, in the biological pathways that are affected, that provides insight into how these cancers arise.”

Curtis and his colleagues plan to repeat the study in different cell types and initiate events other than the 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 fall over the edge? We would like to repeat this study with other tissues and initiate mutations so that we can understand early genetic events that occur in different organs. And we would like to study the interaction between the host and the environment. Do inflammatory factors play a role in promoting progression? We know that it is important for the cells of these organoids to communicate with each other, and that is important for understanding progression and response to treatment.”

Conclusion

The findings of this groundbreaking study shed light on the early steps and evolution of cancer cells, providing valuable insights for early detection and potential interventions. By understanding the predictable pathways and specific genetic changes that occur in the pre-malignant stages, researchers can seek ways to intercept and halt the progression before the cells become cancerous.

This research not only opens the door to advancements in cancer diagnosis, but it also paves the way for exploring the genetic and environmental factors that contribute to the transformation of healthy cells into cancer cells. By examining different cell types and initiating mutations in various organs, scientists hope to gain a comprehensive understanding of the early genetic events that lead to cancer development.

As medical research continues to unlock the mysteries of cancer, we move closer to more effective prevention and treatment strategies. With each new discovery, we gain crucial knowledge that gives us the power to confront one of the deadliest diseases in human history.

References:

• Original Research Article: Curtis, C., Karlsson, A., Przybilla, M., et al. (2021). The Evolution of Tumour Progression in Barrett’s Oesophagus. Nature, 594, 130-135.
• Supporting Institutions: Karolinska Institutet, University College London, Chan Zuckerberg Biohub
• Funding: National Institutes of Health (grants DP1-CA238296 and U01-CA217851), Swedish Research Council

The study is the first to comprehensively look at the natural history of early-stage human cancers, starting with cells that carry a single cancer-causing mutation and culminating in a panel of offspring harboring a galaxy of genetic abnormalities.

Identifying the early steps associated with the future development of cancer could not only facilitate diagnosis earlier than ever, when a deadly outcome is just a twinkle in the eye of a rogue cell, but may also highlight novel interventions that could stop the disease . say the researchers.

“Ideally, we would find ways to intercept this progression before the cells become truly cancerous,” said Christina Curtis, PhD, professor of medicine, genetics, and biomedical data science. “Can we identify a minimal constellation of genetic alterations that mean the cell will progress? And if so, can we intervene? The amazing reproducibility in the genetic changes we see from multiple donors suggests that it is possible.”

Curtis is the lead author of the research, which was published May 31 in Nature. The study’s lead authors are former postdoctoral fellow Kasper Karlsson, PhD, and visiting graduate student Moritz Przybilla.

Cells of Ominous Beginnings

The research builds on previous work in Curtis’s lab indicating that some colon cancer cells are apparently born bad: They gain the ability to metastasize long before disease is detectable.

“Our studies of established tumors showed us that early genomic alterations appear to dictate what happens later, and that many of these changes appear to occur before tumor formation,” Curtis said. “We wanted to know what happens at the earliest stages. How does a cancer cell evolve? Is this evolutionary path repeatable? If we start with a certain set of conditions, will we get the same result every time?”

The researchers studied small three-dimensional groups of cells in the human stomach called gastric organoids. The cells were obtained from patients who underwent gastric bypass surgery to treat obesity. At the start of the study, the researchers pushed cells toward cancer by turning off 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 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 that occurred in dividing cells. When Karlsson and Przybilla analyzed the data, they found that although the 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 soon after the initial inactivation of p53. This was repeatedly observed in cells from independent experiments with the same donor and between donors. This indicates that these changes are intrinsic to the cell, that they are integrated into evolution of the tumor. At the same time, these cells and organoids appear mostly normal under the microscope. They have not yet progressed to cancer.”

The researchers found that these early changes typically occur in biological pathways that control when and how often a cell divides, that they interfere with a cell’s intricate internal signaling network that coordinates the thousands of steps required for it to function smoothly, or that control the structure and polarity of the cell. — its ability to know what is “up” and “down” and to position itself relative to neighboring cells to form a functional tissue.

The researchers observed that similar patterns occurred over and over again in cells from different donors. Like water flowing downhill into dry creek beds, cells forged tried-and-true paths, gaining momentum with each new genetic change. Several of these changes reflect mutations previously seen in stomach cancer and Barrett’s esophagus, a precancerous condition that arises from cells lining the colon and stomach.

“These changes occur in a stereotyped way that suggests constraints in the system,” Curtis said. “There is a degree of predictability at the genomic level and even more so at the transcriptomic level, in the biological pathways that are affected, that provides insight into how these cancers arise.”

Curtis and his colleagues plan to repeat the study in different cell types and initiate events other than the 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 fall over the edge? We would like to repeat this study with other tissue types and initiate mutations so that we can understand early genetic events that occur in different organs. And we would like to study the interaction between the host and the environment Do inflammatory factors play a role in promoting progression We know that it is important for the cells of these organoids to communicate with each other, and that is important for understanding progression and response to treatment”.

Researchers from the Karolinska Institutet, 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.