Scientists uncover a cellular survival mechanism that helps severely damaged tissue regenerate and may also reveal why some cancers return after treatment.
Tissues such as skin, along with the epithelial layers that cover and line many organs, have a remarkable ability to rebuild themselves after extensive damage. Scientists have known about this response, called compensatory proliferation, for roughly half a century. Yet exactly how cells manage to trigger such dramatic regrowth has remained a mystery.
The phenomenon was first documented in the 1970s, when researchers exposed fly larvae to high doses of radiation. Despite major damage to epithelial tissue, the larvae were able to regenerate fully functional wings. Similar regenerative responses have since been observed across many species, including humans.
Now, researchers at the Weizmann Institute of Science say they have identified a molecular mechanism that helps explain how this process works. Their study, published in Nature Communications, points to a surprising role for caspases, enzymes best known for helping destroy cells.
Instead of simply promoting cell death, caspases can apparently help certain cells become resistant to death. Those survivors can then participate in rebuilding damaged tissue and may even become better equipped to withstand future injury. The same ability, however, could have a dangerous downside. Cancer cells may exploit this survival mechanism, potentially contributing to tumors that return in a more aggressive and treatment-resistant form.
The discovery could eventually help researchers develop approaches that encourage healthy tissue repair while also reducing the risk of cancer recurrence.
When Cell Death Machinery Promotes Survival
One of the main ways the body eliminates unwanted cells is through apoptosis, a carefully controlled form of cellular “suicide.” Cells can enter apoptosis when they become old, damaged, or receive molecular signals telling them that their time is up.
The process involves several caspase enzymes. An initiator caspase first activates the pathway, followed by effector caspases that break apart proteins inside the doomed cell.
During the past two decades, however, researchers have discovered that apoptotic caspases are not limited to killing cells. Work by scientists around the world, including the laboratory of Prof. Eli Arama in Weizmann’s Molecular Genetics Department, has shown that these enzymes can also participate in biological processes that are essential for life.
Arama, an early researcher of these nonlethal caspase functions, suspected that they might also help drive compensatory proliferation.
Finding Cells That Start To Die but Survive
To investigate, a team led by Dr. Tslil Braun from Arama’s lab recreated the classic experiment that originally revealed compensatory proliferation. The researchers exposed fruit fly larvae to ionizing radiation, but this time they used modern genetic tools to follow the regeneration of epithelial tissue in far greater detail.
“We set out to identify cells that push the self-destruct button but survive anyway,” Braun explains. “To do this, we used a delayed sensor that reported on cells in which the initiator caspase had been activated but that nevertheless survived the irradiation. This is how we discovered a population of cells we named DARE cells. Not only did these cells survive the irradiation – they multiplied, repaired the damaged tissue and replenished nearly half of it within 48 hours.”
The discovery raised another question. If DARE cells accounted for nearly half of the repaired tissue, where did the rest come from?
The researchers found a second group of cells that were also resistant to death. These cells, called NARE cells, differed in one important way: Their initiator caspase had never been activated.
“We identified another population of death-resistant cells, but unlike DARE cells, they showed no activation of the initiator caspase. We called them NARE cells,” Braun says. “Although NARE cells ultimately contribute to tissue regeneration, they cannot do it alone: When we removed DARE cells from the system, compensatory proliferation disappeared entirely. We also found that dying cells in the tissue play a role in the burst of regeneration – DARE cells were activated by signals from their dying neighbors.”
How DARE Cells Escape Their Death Sentence
The team next investigated why DARE cells could survive radiation levels that caused nearby cells to undergo apoptosis.
They found that the death process begins normally inside DARE cells. The initiator caspase switches on, but the pathway then stalls before the executioner caspases can complete the destruction of the cell.
“We observed that although the initiator caspase is activated in these cells, the cellular death process stops there and does not progress to the next stage,” Arama explains. “We suspected that a protein known as a molecular motor was responsible for this – it can tether the initiator caspase to the cell membrane, preventing it from activating the executioner caspases. Indeed, when we silenced this motor protein, DARE cells proceeded to die and tissue regeneration was impaired. Overactivation of the same motor protein has previously been linked to cancerous tumor growth, which suggests that this might be one of the mechanisms that enables cancer cells to evade apoptosis.”
That connection is especially important because cancer treatments such as radiation often work by damaging tumor cells enough to trigger their self-destruction.
Surviving Radiation Can Make Cells Harder To Kill
Tumors that return following radiation therapy are often more aggressive and more difficult to treat. The researchers therefore wanted to know whether cells that survived an initial dose of radiation could pass their resistance to future generations of cells.
“We wanted to understand whether resistance to death is inherited by the descendants of death-resistant cells that survived the initial irradiation,” Arama says. “We found that when the same tissue is irradiated a second time, the number of cells that die during the first few hours is half that seen after the first irradiation, and most of the dead cells belong to the NARE population. In other words, the descendants of DARE cells were found to be exceptionally resistant – seven times more resistant to cell death than cells in the original tissue. This may help explain why recurrent tumors become more resistant after radiation.”
The findings suggest that surviving an initial assault may leave a lasting biological legacy. Descendants of DARE cells were far more difficult to kill than cells in tissue that had never experienced the first radiation exposure.
That trait could be extremely useful when healthy tissue needs to recover from injury. In cancer, however, the same survival advantage could allow dangerous cells to persist despite treatment.
A Feedback Loop Keeps Regeneration Under Control
Rapid regeneration presents another challenge. Cells need to multiply enough to replace what was lost, but that growth must eventually stop. Otherwise, a repair response could turn into uncontrolled proliferation.
In the final stage of the study, researchers uncovered a signaling system between DARE and NARE cells that appears to maintain this balance.
“DARE cells promote the growth of nearby NARE cells, apparently by secreting growth signals,” Arama notes. “In turn, NARE cells secrete signals that inhibit the growth of DARE cells. In fact, we’ve discovered a negative-feedback loop between the two cell populations that prevents overgrowth.”
This exchange allows the two cell populations to support regeneration while placing limits on excessive growth.
From Tissue Repair to Cancer Treatment
The experiments were conducted in fruit flies, so additional research will be needed to determine how closely the same mechanisms operate in people. Fruit fly models, however, have repeatedly helped scientists uncover fundamental biological processes that were later found to have important parallels in humans.
“We hope that, as has often been the case with fly models, the knowledge gained here can be translated into an understanding of the mechanisms that balance growth and confer resistance to cell death in human tissues,” Arama concludes. “Many cancers originate in epithelial cells that have lost normal growth control, and many traditional cancer treatments aim to cause them to self-destruct through apoptosis. Our findings pave the way for understanding why such treatments sometimes fail and how they could be improved. The results also point toward new ways in which we might be able to accelerate beneficial regeneration of healthy tissue after injury.”
The findings therefore highlight two sides of the same biological survival system. A mechanism that allows healthy tissue to recover from devastating damage could potentially be harnessed to improve healing. At the same time, understanding how cancer cells may take advantage of that mechanism could reveal new strategies for preventing tumors from surviving treatment and returning.
Also participating in the study were Naama Afgin, Dr. Lena Sapozhnikov and Dr. Keren Yacobi-Sharon from Weizmann’s Molecular Genetics Department; Dr. Ehud Sivan from Weizmann’s Life Sciences Core Facilities Department; Prof. Andreas Bergmann from UMass Chan Medical School, Worcester, MA; and Prof. Luis Alberto Baena-Lopez from the Severo Ochoa Molecular Biology Center (CBM), Spain.
Prof. Eli Arama is the incumbent of the Harry Kay Professorial Chair of Cancer Research and head of the Crown Human Genome Center.
