Nuclear ABL Programs Extracellular Vesicles for Transmission of Ionizing Radiation-Induced Bystander Effects

Radiation therapy is used to treat many diseases such as cancer. However, off-targeted side-effects called bystander effects are observed in patients post radiotherapy. Bystander effects are when non-irradiated cells exhibit similar effects as directly irradiated cells. Understanding how these bystander effects are mediated can help improve cancer treatment. Previous work from our lab has shown that extracellular vesicles derived from conditioned media of irradiated mouse embryonic fibroblasts mediate radiation-induced bystander effects by inhibiting clonogenic survival, increase γH2AX, and increase ROS. However, when the protein Abl is mutated so that it no longer can enter the nucleus, the EVs from the conditioned media of these irradiated cells do not cause bystander effects. When nuclear Abl is reconstituted into these mutant cells, the EVs from the conditioned media of these irradiated cells cause bystander effects such as increase γH2AX and increase ROS. This suggests that nuclear Abl is required for extracellular vesicle mediated radiation-induced bystander effects. Abl inhibitors are FDA approved and might be viable treatments to reduce bystander effects in patients undergoing radiation therapy. Additionally, in a paper previously published by our lab, nuclear Abl is required for miR-34c processing. Since EVs can contain miRNAs as cargo, miR-34c could be involved in the nuclear Abl dependent extracellular vesicle mediated radiation-induced bystander effects. This offers another possible treatment target to counter radiation-induced bystander effects