Anastasis, a new mechanism driving cell survival and evolution

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DESCRIPTION (provided by applicant): We recently discovered a new biological phenomenon, which we call anastasis (Greek for “rising to life”). Overturning the current dogma that cell death is irreversible, we found that a variety of normal and cancer cell types can reverse the process, survive, and proliferate. This reversibility takes place even after cells experience events widely believed to be points of no return, including activation of caspase enzymes and widespread DNA damage. Notably, while most cells fully recover and repair their damaged DNA, some cells retain mutations, and this increases the frequency of oncogenic transformation. The discovery of anastasis has at least five paradigm-shifting implications. First, we suggest that anastasis represents a previously unknown cause of cancer, so inhibiting anastasis should prevent cancer. Anastasis could also offer an explanation for the longstanding observation that repeated injury increases the incidence of cancer. Second, we propose that anastasis allows tumor cells to escape chemotherapy and evolve drug resistance. Therefore, inhibiting anastasis may enhance the effectiveness of chemoand radiation therapies and prevent relapses. Third, salvaging cells on the brink of death via anastasis may limit permanent tissue injury due to transient environmental stresses or toxin exposures. Consequently, enhancing anastasis may promote tissue regeneration. Fourth, we posit that anastasis is a cell survival mechanism that protects cells that are difficult to replace such as neurons in the adult brain or heart muscle cells, so promoting anastasis could prevent or slow degenerative diseases. Fifth, we propose that the survival of germ cells with mutations acquired through anastasis provides a mechanism to enhance genetic diversity precisely when animals are exposed to stressful environmental conditions. This could accelerate adaptation to changing environments during evolution. Here we propose to test these ideas. We designed a biosensor that will allow us to identify and track cells that undergo anastasis in vivo by creating permanent expression of a reporter such as GFP in cells that survive caspase activation. Using this biosensor in mice we propose to test the hypotheses that transient injuries and stresses induce anastasis, that anastasis causes cancer and allows tumor cells to evade therapies and develop drug resistance. Using the biosensor in Drosophila, we will test the hypothesis that anastasis enhances genetic diversity in the population. In addition, we propose to decipher the molecular mechanisms that allow cells to reverse the dying process and survive and identify molecular approaches to inhibit or enhance anastasis. The successful completion of this project offers the potential to develop revolutionary new therapies for cancer, neurodegenerative diseases, and heart failure, and provide new insight into the mechanisms of evolution by natural selection.