Scientists have uncovered a cellular survival mechanism that aids severely damaged tissue in regenerating and may explain why some cancers recur after treatment. While the phenomenon of compensatory proliferation—the ability of tissues like skin and organ linings to rebuild after extensive damage—has been documented since the 1970s, the exact molecular triggers remained a mystery until researchers at the Weizmann Institute of Science identified a surprising role for caspases, enzymes typically associated with cell death. 
Published in Nature Communications, the study reveals that instead of solely promoting cell death, caspases can help certain cells become resistant to destruction, allowing them to rebuild tissue or potentially enabling cancer cells to withstand treatment. 
The research team, led by Dr. Tslil Braun in the laboratory of Prof. Eli Arama, investigated how these enzymes function beyond apoptosis, noting that while initiator caspases usually activate pathways that lead to cell destruction, they can also drive essential biological processes. "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." 
However, when researchers questioned the origin of the remaining repaired tissue, they identified a second group called NARE cells, which were death-resistant but had never activated their initiator caspase. "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." The study further detailed that while DARE cells initiate the death pathway, it stalls before executioner caspases can destroy 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." This finding is critical because recurrent tumors often become more aggressive after radiation therapy. 
Arama notes, "We wanted to understand whether resistance to death is inherited by the descendants of death-resistant cells that survived the initial irradiation." 
The team found that when tissue is irradiated a second time, the number of dying cells drops significantly, with descendants of DARE cells proving "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." To prevent this rapid regeneration from turning into uncontrolled growth, the researchers discovered a balancing signaling system: "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.