Project 1: Temporal Signaling Cascade in Radiation-induced Intercellular Communication
Leader: Kathryn D. Held
Radiation therapy is a local therapy, yet cellular, experimental animal and even human studies have shown that effects of
the radiation can be seen in un-irradiated cells near irradiated cells ("bystander" effects) or at substantial distances (abscopal or "out of field" effects). Furthermore,
newer data show that un-irradiated cells can alter responses of irradiated cells. Details of how signals are initiated and transmitted between irradiated tumor cells and
non-irradiated normal cells and tissues are not clear. Mechanistic studies suggest that multiple early processes are involved that together form a communications network t
ransmitting the signals. This project will test the novel overall hypothesis that early bystander signaling from irradiated tumor cells occurs in several "waves" that differ
with regards to timescales and signaling pathways involved, but all coalesce to create an environment of increased oxidative stress and inflammation that predisposes normal
tissues to cancer development or late damage and may alter tumor responses.
The project takes advantage of the unique strength of a microbeam system to irradiate specific cells or regions of cells in short times, coupled with powerful microscopy approaches to follow propagation of changes in unirradiated cells as a function of time and space. The project will use 2D and 3D models of breast and brain containing multiple cell types, including both cancer stem-like and non-stem cells and normal parenchymal and fibroblast cells, thus providing critical information on molecular mechanisms for the other Projects. A series of 4 inter-related aims are proposed to address the central hypothesis. The Project has high significance to both use of radiation to treat cancer as well as potential for late tissue responses to low dose radiation. The results will advance the field by providing critical understanding of the processes and timescales of propagation of radiation-initiated signals that is critical to enable development of pharmacologic countermeasures that target specific pathways at relevant times to decrease late normal tissue damage and cancer development.