Scientists discover a cell survival mechanism that helps regenerate severely damaged tissue 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 after significant damage. Scientists have known about this response, called compensatory proliferation, for about half a century. However, exactly how the cells manage to trigger such dramatic growth remains a mystery.
The phenomenon was first documented in the 1970s, when researchers exposed fly larvae to high doses of radiation. Despite significant damage to the epithelial tissue, the larvae were able to regenerate fully functional wings. Similar regenerative responses have since been observed in 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. His study, published in Nature Communicationspoints to a surprising role for caspases, enzymes best known for helping to 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 be better equipped to resist future injuries. However, the same ability could have a dangerous drawback. Cancer cells can take advantage of this survival mechanism, potentially contributing to tumors returning in a more aggressive and treatment-resistant form.
The discovery could eventually help researchers develop approaches that encourage the repair of healthy tissues while reducing the risk of cancer recurrence.
When the 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 age, become damaged, or receive molecular signals that tell them their time is up.
The process involves several caspase enzymes. An initiator caspase first activates the pathway, followed by effector caspases that break down proteins within the doomed cell.
However, over the past two decades, researchers have discovered that apoptotic caspases do more than just kill cells. Work by scientists around the world, including the laboratory of Prof. Eli Arama in the Weizmann Department of Molecular Genetics, has shown that these enzymes can also participate in biological processes essential for life.
Arama, one of the first investigators of these nonlethal functions of caspases, suspected that they might also help drive compensatory proliferation.
Finding cells that begin to die but survive
To investigate, a team led by Dr. Tslil Braun of 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 much greater detail.
“We set out to identify cells that press the self-destruct button but survive anyway,” explains Braun. “To do this, we used a delayed sensor that reported on cells in which the initiating caspase had been activated but which nevertheless survived the irradiation. This is how we discovered a population of cells that we call DARE cells. These cells not only survived the irradiation, but multiplied, repaired the damaged tissue and replaced almost half of it within 48 hours.”
The discovery raised another question. If DARE cells accounted for almost 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 the DARE cells, they did not show activation of the initiator caspase. We call them NARE cells,” says Braun. “Although NARE cells ultimately contribute to tissue regeneration, they cannot do it alone: when we removed DARE cells from the system, compensatory proliferation disappeared completely. 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
Next, the team investigated why DARE cells could survive radiation levels that caused nearby cells to undergo apoptosis.
They discovered that the death process normally begins within DARE cells. The initiator caspase is activated, but the pathway stops before the executioner caspases can complete the destruction of the cell.
“We observed that although the initiator caspase is activated in these cells, the cell death process stops there and does not advance to the next stage,” explains Arama. “We suspected that a protein known as a molecular motor was responsible for this: it can bind the initiator caspase to the cell membrane, preventing it from activating executioner caspases. In fact, 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 the growth of cancerous tumors, suggesting that this could be one of the mechanisms that allows 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 may make cells harder to kill
Tumors that come back after radiation therapy are usually more aggressive and more difficult to treat. Therefore, the researchers wanted to know whether cells that survived an initial dose of radiation could pass on their resistance to future generations of cells.
“We wanted to understand whether death resistance is inherited by the descendants of death-resistant cells that survived the initial irradiation,” says Arama. “We found that when the same tissue is irradiated a second time, the number of cells that die during the first hours is half of what is observed after the first irradiation, and the majority of dead cells belong to the NARE population. In other words, the descendants of the DARE cells were found to be exceptionally resistant: seven times more resistant to cell death than cells from the original tissue. This may help explain why recurrent tumors become more resistant after radiation.”
The findings suggest that surviving an initial attack can leave a lasting biological legacy. The descendants of the DARE cells were much more difficult to kill than the tissue cells that had never experienced the first exposure to radiation.
That trait could prove extremely useful when healthy tissue needs to recover from injury. However, in cancer, 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, the researchers discovered 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 have discovered a negative feedback loop between the two cell populations that prevents excessive growth.”
This exchange allows the two cell populations to support regeneration while imposing 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. However, fruit fly models have repeatedly helped scientists uncover fundamental biological processes that were later found to have important parallels in humans.
“We hope that, as has often happened 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,” concludes Arama. “Many cancers originate in epithelial cells that have lost normal control of growth, and many traditional cancer treatments aim to cause them to self-destruct through apoptosis. Our findings pave the way to understanding why these treatments sometimes fail and how they could be improved. The results also point to new ways in which we could accelerate the beneficial regeneration of healthy tissue after injury.”
Therefore, the findings highlight two sides of the same biological survival system. A mechanism that allows healthy tissue to recover from devastating damage could be harnessed to improve healing. At the same time, understanding how cancer cells can take advantage of that mechanism could reveal new strategies to prevent tumors from surviving treatment and coming back.
Also participating in the study were Naama Afgin, Dr. Lena Sapozhnikov, and Dr. Keren Yacobi-Sharon from the Weizmann Department of Molecular Genetics; Dr. Ehud Sivan of the Weizmann Life Sciences Core Facilities Department; Prof. Andreas Bergmann of UMass Chan School of Medicine, Worcester, MA; and Prof. Luis Alberto Baena-López from the Severo Ochoa Molecular Biology Center (CBM), Spain.
Prof. Eli Arama is the holder of the Harry Kay Chair in Cancer Research and director of the Crown Human Genome Centre.