Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium

Area of Science:

• Radiation Oncology
• Molecular Biology
• Cancer Research

Background:

• Ataxia telangiectasia (ATM) is a genetic disorder characterized by extreme sensitivity to ionizing radiation.
• ATM kinase inhibitors show potential for sensitizing tumor cells to radiation therapy but raise concerns about normal tissue toxicity.
• The role of endothelial cell death in tumor response and radiation side effects is not fully understood.

Purpose of the Study:

• To investigate whether endothelial cell-specific ATM deletion sensitizes tumors and normal tissues to radiation.
• To determine the impact of ATM loss in endothelial cells on sarcoma radiosensitivity and radiation-induced normal tissue damage.

Main Methods:

• Development of dual recombinase technology (FlpO and Cre) to generate endothelial cell-specific Atm deletion in mouse sarcomas.
• Assessment of sarcoma response to radiation following ATM deletion in endothelial cells.
• Evaluation of radiation-induced myocardial necrosis in mice with ATM-deleted quiescent endothelial cells.

Main Results:

• Endothelial cell-specific ATM deletion enhanced sarcoma response to radiation.
• ATM deletion in quiescent cardiac endothelial cells did not sensitize mice to radiation-induced myocardial necrosis.
• Blocking cell cycle progression reversed the radiosensitizing effect of ATM loss in tumor endothelial cells.

Conclusions:

• ATM deletion sensitizes endothelial cells to radiation, but this effect is dependent on cell cycle progression.
• Targeting ATM in proliferating tumor endothelial cells may enhance radiation therapy efficacy without increasing normal tissue toxicity.
• These findings highlight the importance of endothelial cell cycle status in determining radiosensitivity.