Chemotherapy and radiotherapy kill cancer cells by inducing various types of cell death including apoptosis (Greek for falling to death), which is a natural cell suicide process. Primary cancers often exhibit dramatic initial responses to such therapies. However, most metastatic cancers, such as lung and pancreatic cancers, inevitably recur, leading to treatment failure. Apoptosis is generally assumed to be an intrinsically irreversible process. However we recently discovered an unexpected natural reversibility of execution-stage apoptosis in variety of human cancer cells and mouse primary cells. Dying cells can reverse apoptosis even after caspase-3 activation, which is widely believed to be the point of no return. We named this new recovery process anastasis (Greek for rising to life). Simply removing the apoptosis inducer can allow dying cells to reverse apoptosis, indicating that anastasis is a natural cellular recovery process. Notably, some cells that reverse apoptosis and harbor DNA damage appear to be transformed based on colony formation assays, and they have a higher frequency of chromosome rearrangements, suggesting that anastasis may promote survival of cells with oncogenic potential. Our findings lead to fundamental key questions: can reversal of apoptosis occur in vivo after treatment with apoptosis-inducing cancer therapies, and if so, can anastasis contribute in cancer recurrence after the therapies? In case true, anastasis would be a novel therapeutic target in cancer treatment. Recently, we have successfully developed a highly sensitive in vivo biosensor that allows us to identify cells that have undergone anastasis in Drosophila melanogaster.
In Aim 1, we will develop new mammalian versions of the biosensor, and generate transgenic mice for future use to detect anastasis in vivo.
In Aim 2, we propose to identify key regulators of anastasis. The proposed work has potential to uncover novel mechanisms of tumor development and evasion, and to provide new insights into the treatment of cancers by targeting anastasis.

Public Health Relevance

Cancer recurrence is a major problem in the clinical management of most types of cancer, but its mechanism is still unclear. We will create tools to examine the contribution of anastasis in cancer cells to recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
5K22CA204458-03
Application #
9751798
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Korczak, Jeannette F
Project Start
2017-08-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Tang, Ho Man; Fung, Ming Chiu; Tang, Ho Lam (2018) Detecting Anastasis In Vivo by CaspaseTracker Biosensor. J Vis Exp :