Starvation improves epithelial fitness by selectively extruding DNA damaged cells

Living tissues are not static walls; they are dynamic, breathing communities of cells that must constantly balance growth with removal to stay healthy. In the outer layers of our bodies, known as epithelia, cells work tightly together to form protective barriers. To keep these barriers intact while replacing old cells, the tissue has a precise mechanism for ejecting unwanted neighbors. Usually, this process is triggered when a cell becomes overcrowded or damaged, signaling its neighbors to squeeze it out of the layer. This ejection, called extrusion, is a vital housekeeping duty that prevents inflammation and stops damaged cells from turning into tumors. While scientists have long known that cells can be pushed out when they run out of energy or when they are physically crowded, a new study reveals a more targeted and rapid response to hunger.

Researchers at King's College London and the Francis Crick Institute discovered that when epithelial cells are suddenly deprived of essential nutrients like glucose and glutamine, the tissue does not simply weaken. Instead, it launches a highly selective cleanup operation. They found that starvation triggers a rapid, self-limiting wave of extrusion that specifically hunts down and removes cells carrying DNA damage or those that have become cancerous. The team, led by Jody Rosenblatt, observed that within one hour of removing nutrients from the culture, the cells began to eject their damaged neighbors at a much higher rate than usual. This wave peaked at two hours and then stopped, returning the tissue to a normal state. The researchers named this phenomenon STICE, or Starvation-Induced Cell Extrusion.

What makes this discovery significant is how different it is from the usual way cells are removed. Under normal conditions, when cells are crowded, the tissue relies on a mechanical sensor called Piezo1 to detect pressure and eject the cell with the least amount of energy. However, the new study showed that STICE does not use this mechanical sensor. Even when the researchers blocked the Piezo1 channel, the starvation-induced ejection continued. Furthermore, the cells being removed were not just the ones with the least energy; they were specifically the ones with broken DNA or genetic mutations. By staining the cells for markers of DNA damage, the team saw that the cells being ejected were heavily marked with these damage signals, while the healthy cells remaining in the layer were largely untouched.

The mechanism behind this selective removal involves a surprising twist on how cells handle their internal waste. Normally, when a cell is starving, it activates a recycling process called autophagy, where it digests its own damaged parts to survive. The researchers expected the cells undergoing extrusion to use this same recycling method. Instead, they found that the cells destined for removal took a different path. They used specific proteins to move their lysosomes—the cell's waste disposal bags—directly to the outer membrane. Rather than fusing with the lysosome to digest the contents, these cells pushed the lysosomes out of the cell entirely. This process, known as exocytosis, allowed the damaged cells to release signals that told their neighbors to squeeze them out. Crucially, this process required a protein called p53, which acts as a master regulator for DNA damage. When the researchers blocked p53, the starvation-induced extrusion stopped, proving that the tissue uses this specific pathway to identify and eject only the most compromised cells.

The result of this targeted cleanup is a healthier, more resilient tissue. After the wave of extrusion, the remaining layer of cells was significantly better at surviving further attacks, such as exposure to UV light or chemicals that usually cause cell death. The study showed that by removing the weak links, the tissue as a whole became stronger. The researchers also tested this on cells that had been genetically modified to carry a mutation common in aggressive cancers, known as KRas. When these cancer-prone cells were starved, they were rapidly and selectively ejected from the layer, while the healthy cells stayed put. This suggests that the body has a built-in defense mechanism that can recognize and remove dangerous cells when nutrients are scarce.

The findings offer a new perspective on how tissues maintain their integrity during stress. While the body often relies on individual cells to recycle their own components to survive hunger, this study shows that tissues can also act as a collective unit to eliminate substandard members. The researchers propose that STICE acts as a tissue-level version of autophagy: instead of fixing the broken parts inside a single cell, the tissue fixes the whole by removing the broken cell entirely. Although the study was conducted in cell cultures, the authors note that similar starvation responses have been seen in simple sea creatures, suggesting this might be an ancient and conserved way for life to protect its barriers. The work opens the door to understanding how fasting or dietary changes might influence tissue health, potentially offering new ways to support the body's natural ability to clear out damaged or pre-cancerous cells.