Detecting Reversal of Apoptosis in Cancer Cells in Mice

Detecting Reversal of Apoptosis in Cancer Cells in Mice Project Summary Targeting apoptotic pathways is one of the most important therapeutic strategies for cancer treatments, and primary cancers often exhibit dramatic initial responses to such treatments. However, most metastatic cancers inevitably recur, leading to treatment failure. The classical view of apoptosis has

long assumed that, once initiated, this cell suicide process is irreversible. Challenging this assumption is our recent highly original discovery that apoptosis can be reversible, even at late stages, in multiple human cancer cell lines in vitro. We named this cell recovery mechanism “anastasis”, which means

“rising to life” in Greek. Removal of a death stimulus is sufficient to allow anastasis to occur, thus indicating that anastasis is an intrinsic recovery phenomenon. We hypothesize that anastasis is an unexpected escape tactic used by cancer cells to survive cell-death-inducing cancer therapy, thereby

causing cancer recurrence. If this hypothesis is true, anastasis would be a novel therapeutic target for suppressing cancer recurrence and progression. However, anastasis in cancer cells in vivo has yet to be demonstrated, and the consequences of anastasis remain undiscovered. To detect anastasis in live

animals, we have successfully developed a new biosensor to label anastatic cells in fruit flies, by fluorescently tagging cells that have reversed apoptosis. This permanent tag is a unique tool for detecting and following the consequences of anastasis in vivo. Here, we will apply the similar strategy

to detect and track anastasis in cancer cells in mice. By incorporating biosensor-expressing human cancer cells with three clinically relevant xenograft mouse models of cancer relapse, we will determine whether anastasis occurs in cancer cells in vivo, and if identified, whether it contributes to recurrence

after anti-cancer therapy. Our results will lay a strong foundation for developing anastasis-targeting anti-cancer therapy, by generating essential animal models for studying the consequences of anastasis, and by revealing the therapeutic potential of harnessing anastasis to suppress cancer recurrence.