Genetic Regulators of ER Stress-induced Apoptosis in Pediatric Malignancies

One major cause of death from cancer occurs when tumor cells leave their native location and colonize new areas in the body, causing disruption of normal biological events in that tissue or organ system. New methods of killing these cells are required, and one promising approach is to take advantage of the "stressed" nature of cancer cells, specifically killing them while leaving surrounding cells unharmed. Researchers have discovered that a major stress encountered by migrating cancer cells occurs through a structure in the cell called the endoplasmic reticulum, or "ER." ER stress often triggers death within normal cells, but cancer cells somehow manage to maintain their survival. The mechanisms that cells use to decide whether to survive or die following ER stress are poorly understood, warranting further research into these basic biological decisions. Previous studies in living systems including yeast and worms have been very informative for learning about the basic processes of ER stress, but the machinery that yeast and worm cells use to die is much different than that of humans. Additionally, mice, which are highly related to humans, are very laborious to use for discovering new molecules involved in ER stress-induced cell death. Thus, there is need of a new model system for finding the critical molecules that differentiate whether cells survive or die following ER stress. Here, I propose to use the zebrafish, a small aquatic animal largely related to humans in its cell death machinery, for discovering new components that mediate how ER-stressed cells make the life versus death decision. Having established a regimen for inducing ER stress-induced cell death in zebrafish, I now propose to find the molecules that allow certain cells to survive in the animal while other cells die. I will then explore how these same molecules may be involved in T cell acute lymphoblastic leukemia (T-ALL) and neuroblastoma, two common childhood cancers, by utilizing zebrafish generated in our laboratory that harbor these diseases. Discovering new molecules in the ER stress pathway should facilitate the development of novel therapies for treating T-ALL, neuroblastoma, and other prevalent childhood cancers.