Cellular plasticity and regeneration after radiation damage in Drosophila Cellular plasticity and regeneration after radiation damage in Drosophila More than half of cancer patients receive ionizing radiation (IR), alone or as a component of their treatment (www.cancer.org). IR induces DNA damage to kill cells. Surviving cancer cells could, however, regenerate the tumor, leading to treatment failure. While we understand much about how irradiated cells repair damaged DNA or undergo cell death, how tumors regenerate remains incompletely understood. The overall objective of our research program is to understand how tissues regenerate after damage by IR in vivo in a multicellular context, to identify and characterize the genes and proteins involved in this process, and to develop genetic and chemical tools to manipulate the function of these regulators. Drosophila melanogaster has been an ideal organism for this work because of precision lineage tracing tools, amenability to genetic and chemical screens, and the ease of molecular analysis to uncover gene function. Cell death and regeneration in Drosophila and vertebrates share conserved genetic and molecular features. Chemical modulators of IR-induced regeneration we discovered in Drosophila behave similarly in human cancer models. Therefore, what we learn in Drosophila is likely to apply to humans. Regeneration of Drosophila larval organs called imaginal discs occurs without a dedicated stem cell pool. My lab identified a previously unknown mode of regeneration in Drosophila larval wing discs whereby a specific subset of columnar epithelial cells in the future hinge region change fate to acquire stem cell-like properties. IR-induced cell fate plasticity in Drosophila parallels the increasingly appreciated ability of cancer treatments including IR to induce stem cell-like properties in non-stem cancer cells, a phenomenon implicated in tumor re-growth and treatment failure. Progress in the current funding period includes the finding that IR- induced fate change requires ribosome biogenesis and apoptotic caspase activity in hinge cells that are nonetheless refractory to IR-induced apoptosis. These findings lead to a conceptually innovative working model in which changes in the proteome through non-lethal caspase activity and increased translation capacity act on top of changes to the transcriptome to affect cell fate change. Rigorous testing of this model will guide our future activities that will include asking why cells change fate into one cell type but not another. Technical innovation is inherent in quantitative assays for IR-induced cell fate plasticity. The ultimate goal is a comprehensive understanding of how changes in the translated transcriptome are coordinated to promote IR- induced cell fate plasticity in the context of organism development. What we learn will not only increase our understanding of regeneration after IR damage but also will identify mechanisms that may be modulated to i...