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.
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.