丙酮酸代谢的重编程克服肠道干细胞放射敏感性的性别特异性差异并改善腹部照射的治疗比

Our study was done to elucidate the mechanism of sex-dependent differences in radiotherapy (RT) response in males versus females, and then utilize this mechanism to help prevent intestinal radiation toxicity. More than 50% of patients with gastrointestinal (GI) cancers undergo abdominal radiotherapy. However, intestinal epithelial radiosensitivity is a major limiting factor to delivering a tumoricidal dose. Personalized differences, including sex-specific differences in radiosensitivity, is one of the key determining factors in radiotherapy outcome. Using a mouse model of abdominal irradiation and a human intestinal organoid model, we previously demonstrated that healthy male intestinal stem cells are more radiosensitive than females due to higher rates of oxidative phosphorylation (OXPHOS) and production of reactive oxidative species (ROS). In the present study, we demonstrate that these higher rates of OXPHOS in males are due to increased expression of the Mitochondrial Pyruvate Carrier (MPC), which transports pyruvate into the mitochondria for flux through the TCA cycle, and, ultimately, the OXPHOS pathway. Genetic deletion of the MPC in Lgr5-EGFP-positive ISCs increases ISC survival following the reduction in radiation-induced mitochondrial pyruvate oxidation in both male and female organoids. In both human intestinal organoids and a mouse model of radiation-induced gastrointestinal syndrome, treatment with MPC inhibitor, UK5099, normalized these differences in radiation responses between males and females. Moreover, our study in a mouse model of pancreatic adenocarcinoma also establishes UK5099 as a radio-modulator for pancreatic cancer, as combination of RT+ UK5099 treatment significantly reduces tumor growth and alters the immunosuppressive tumor immune microenvironment compared to irradiated control. These findings clearly suggest that pyruvate metabolism and MPC can be a potential target to promote therapeutic ratio of abdominal radiotherapy.