Ionization radiation (IR) is a major treatment module for cancer because of its ability to induce cell death. Understanding mechanisms that make cells more or less sensitive to killing by IR is an essential first step towards making radiotherapy more effective. The goal of this proposal is to understand one such mechanism. Specifically, the proposal will address a mechanism by which dying cells protect nearby cells from IR-induced apoptosis, using Drosophila as a model. Preliminary studies have uncovered two key players in this mechanism, a receptor tyrosine kinase (RTK) and a microRNA. The goal of this funding period is to identify additional molecular components, in order to reach a complete understanding of this novel effect of dying cells.
The Aims are: 1. Investigate whether candidate gene products that underlie the protective effect are required in dying cells or in protected cells 2. Identify the signal that activates the RTK. 3. Identify the remaining components of the signaling pathway in a forward genetic screen. The impact of this project will be the advancement of the field through a molecular understanding of a novel response to cell death. Another potential impact could be the identification of a similar response in clinically relevant mammalian systems in future studies. If conserved in human, a mechanism by which dying cells render nearby cells more resistant to IR could have profound clinical implications, especially in settings where radiotherapy is applied sequentially with cytotoxic chemotherapy.

Public Health Relevance

Ionizing radiation is one of three main modes of cancer therapy, the others being chemotherapy and surgery. Anti-cancer activity of radiation is based on induction of apoptosis. Standard of care for many cancers is the combinatorial use of a cytotoxic chemotherapeutic agent(s) and radiation. This proposal is to study a phenomenon in which prior cell killing results in resistance of surviving cells to subsequent exposure to radiation. If conserved in mammals, such a phenomenon could have implications for clinical practices based on sequential use of cytotoxic agents and radiation. The study will use Drosophila melanogaster as an experimental model. Because of excellent conservation of gene function between Drosophila and human, what we learn may allow us to design more effective use of radiation for therapy against human cancers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Maas, Stefan
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Verghese, Shilpi; Su, Tin Tin (2018) Ionizing radiation induces stem cell-like properties in a caspase-dependent manner in Drosophila. PLoS Genet 14:e1007659
Su, Tin Tin (2018) Cellular plasticity, caspases and autophagy; that which does not kill us, well, makes us different. Open Biol 8:
Duronio, Robert J; O'Farrell, Patrick H; Sluder, Greenfield et al. (2017) Sophisticated lessons from simple organisms: appreciating the value of curiosity-driven research. Dis Model Mech 10:1381-1389
Verghese, Shilpi; Su, Tin Tin (2017) STAT, Wingless, and Nurf-38 determine the accuracy of regeneration after radiation damage in Drosophila. PLoS Genet 13:e1007055
Verghese, Shilpi; Su, Tin Tin (2016) Drosophila Wnt and STAT Define Apoptosis-Resistant Epithelial Cells for Tissue Regeneration after Irradiation. PLoS Biol 14:e1002536
Su, Tin Tin (2015) Non-autonomous consequences of cell death and other perks of being metazoan. AIMS Genet 2:54-69
Stickel, Stefanie A; Gomes, Nathan P; Frederick, Barbara et al. (2015) Bouvardin is a Radiation Modulator with a Novel Mechanism of Action. Radiat Res 184:392-403
Xing, Yalan; Su, Tin Tin; Ruohola-Baker, Hannele (2015) Tie-mediated signal from apoptotic cells protects stem cells in Drosophila melanogaster. Nat Commun 6:7058
Stickel, Stefanie; Gomes, Nathan; Su, Tin Tin (2014) The Role of Translational Regulation in Survival after Radiation Damage; an Opportunity for Proteomics Analysis. Proteomes 2:272-290
Stickel, Stefanie; Su, Tin Tin (2014) Oncogenic mutations produce similar phenotypes in Drosophila tissues of diverse origins. Biol Open 3:201-9

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