Yale University researchers are diving into the complex world of cancer at its very inception, studying how the body responds to potentially cancer-causing mutations in living animals. Their focus? Tolerance.
It’s well-known that most biological organisms, including humans, accumulate genetic mutations over time, many of which could lead to cancer. However, not all of these mutations progress into full-blown disease. The body tolerates many mutated cells and never develops cancer. The critical question is: Why? What factors determine whether a mutated cell is eliminated or grows into a dangerous cancer?
To answer these questions, a team led by Yale‘s Valentina Greco and Rachel Perry investigated how the body reacts to different types of mutations in skin stem cells. Using mouse models, the team tracked the “competition” between normal and mutated cells in the skin over time.
Their findings provide new insights into the body’s early responses to cancer-causing mutations. They focus on metabolic changes that occur before tumors can form.
The research team discovered that the body’s first line of defense against tolerated mutations is an immediate metabolic shift, known as a “redox response.” This process involves a rapid drop in the redox ratio. This chemical reaction indicates an increase in oxidation within cells, acting as a marker of altered metabolism, particularly in how cells process glucose.
Anupama Hemalatha, a former associate research scientist in Greco’s lab and the study’s first author, explained the importance of this finding. “We saw that metabolism responds very quickly to cancer mutations in the skin stem cell layer,” she said. “Using our multiphoton imaging technique, we captured these early metabolic changes in living skin cells of mice and tracked them over time.”
Determining the timing of cancer mutations
What stood out, however, was the nature of the redox response itself. Traditionally, cancer cells are known for their high glucose consumption through glycolysis — a process akin to chopping a tree into pieces to use the energy — and reduced reliance on oxidative metabolism as part of the Warburg effect.
However, the researchers uncovered an unexpected twist: the mutation that persisted in the skin increased metabolism through glycolysis and oxidation pathways, contrary to the Warburg effect. In contrast, a mutation typically eliminated from the skin increased glucose oxidation, even as glycolysis dropped.
Tracking Mutated Cells Over Time
After identifying these metabolic changes, the researchers observed the progress of two specific mutations. One was typically eliminated from the skin over time, while the other remained but did not lead to disease.
The mutation usually removed from the skin maintained a lower redox ratio throughout the process than healthy cells. However, the persistent mutation saw its redox ratio increase and “flatten out,” bringing it in line with neighboring healthy cells. This shift signals a transition from a potentially harmful mutation to one the body could tolerate.
A New Path for Cancer Treatment?
The researchers pushed their investigation further by treating the mice with Metformin, a drug known for inhibiting early metabolic changes. The results were striking. The treatment reversed the behavior of both mutations. Mutated cells that had been expanding were halted, while mutated cells that would usually be eliminated were no longer efficiently removed from the skin.
“This suggests that the early metabolic response triggered by cancer-causing mutations plays a pivotal role in determining whether those mutations are tolerated or lead to disease,” said Greco, the Carolyn Walch Slayman Professor of Genetics and of Cell Biology and a Howard Hughes Medical Institute Investigator. “If these metabolic shifts didn’t occur, many downstream effects, including the mutation’s progression, might not happen.”
Next Steps: Investigating Cancer’s Unfolding Process
The team’s next step is to explore how the body responds when neighboring cells do not tolerate mutations. They hope to determine whether the same redox response occurs when mutations are actively rejected by the body, potentially revealing new targets for cancer therapies.
With cancer research continuously evolving, Yale’s findings offer a new avenue for understanding how the body navigates the fine line between tolerance and disease. This knowledge could eventually guide more effective treatments for cancer.
Journal Reference:
- Hemalatha, A., Li, Z., Gonzalez, D.G. et al. Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations. Nat Cell Biol (2025). DOI: 10.1038/s41556-024-01574-w