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1. Cellular plasticity after radiation damage

Cancer cells that survived radiation treatment can regenerate the tumor, leading to treatment failure. We are using Drosophila to uncover mechanisms for tissues regeneration after radiation damage. We identified a subset of epithelial cells in the larval wing disc that can change their identify to help replace another cell type lost to radiation damage (Verghese & Su, PLoS Biology, 2016). Using a combination of genome-wide analyses and tissue-specific knockdowns, we are discovering new mechanisms that ensure fidelity (Verghese & Su, PLoS Genetics, 2017) and cell fate plasticity during regeneration (Ledru et al., 2022). Current efforts on this project are to understand the role of translational control and long range signaling in fate change. Working on this project are Nate, Cait and Michael.

2. Non lethal role of apoptotic caspases

Unexpectedly, we found that apoptotic caspases are required in the regenerating cells where we hypothesize they play a non-lethal role in cell fate plasticity during regeneration (Verghese and Su, PloS Genetics, 2018). To test this hypothesis, we have been using fluorescence reporters that mark cells that activated apoptotic caspases but did not die (made by Tang, Hardwick and Montell labs). We call them 'cells with X-ray induced past caspase activity' or XPAC. We identifed genes that regulate the survival of XPAC cells and found that one consequence of past caspase activity is to reduce genome instability in tissues that are recovering from X-ray damage (Colon-Plaze and Su, under revision). Working on this project is Sarah.

3. Genome integrity after radiation and heavy metal exposure

Ionizing Radiation such as X-rays causes DNA breaks. Cells will try to repair them but not always perfectly so that the resulting genome has permanent changes (mutations). We have been monitoring these using Loss of Heterozygosity (LOH) assays. These monitor the loss of one copy of a gene in a cell that has just that copy to begin with (a heterozygote). We have uncovered p53-dependent and p53-dependent mechanisms that cull cells with LOH (Brown et al., PLoS Genetics, 2020). We conducted a focused RNAi screen and identified E2F1 and JNK as additional regulators (Brown and Su, under revision). In the summer of 2023, we initiated a project wherein we use the same assays to ask if environmental heavy metals also cause permanent changes to the genome. We are particularly interested in combinations of lead, cadmium and arsenic because these are found in mining waste in ÃÛÌÇÖ±²¥. Working on this project are Barb and Elle.

4. Chemical modulators of radiation sensitivity

Drosophila larvae have an amazing capacity to regenerate. Even after half of the cells in larval organ precursors have been killed with X-rays, the remaining cells can regenerate to produce a healthy, fertile adult. We are using this system to screen for small chemical molecules that inhibit regeneration after radiation damage, thereby enhancing the killing effect of radiation. Derivative of a molecule we found in Drosophila has been shown to enhance the effect of radiation and to reduce the growth of tumors from human head and neck cancer patients grown in mice (Keysar et al., 2020). Our latest accomplishment in this project is the successful development of a high-throughput screen with a clonogenic endpoint to identify new chemical modulators of radiation sensitivity in seven types of human cancer (Gomes et al., 2023). Working on this project are Barb and Nate.