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.

Public Health Relevance

50-70 billion cells in the human body die each day. In contrast to the prevailing dogma, we recently discovered a surprising ability of cells to reverse the death process at a very late stage. Here, we propose to study the physiological consequences and molecular mechanisms of this survival mechanism in order to develop revolutionary new therapeutic approaches to degenerative diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1CA195760-01
Application #
8750779
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50))
Program Officer
Salnikow, Konstantin
Project Start
2014-09-24
Project End
2019-07-31
Budget Start
2014-09-24
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$767,500
Indirect Cost
$267,500
Name
University of California Santa Barbara
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106