Therapeutic radiation exposure of the abdomen during childhood induces chronic adipose tissue dysfunction.

Abstract

BACKGROUND\nChildhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors.\n\n\nMETHODS\nWe performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Study participants underwent abdominal subcutaneous adipose biopsies to obtain tissue for bulk RNA-sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.\n\n\nRESULTS\nIrradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion. This signature includes activation of the TREM2-TYROBP network, a pathway described in diseases of chronic tissue injury. Radiation exposure of adipose is further associated with dysregulated adipokine secretion, specifically a decrease in insulin-sensitizing adiponectin and an increase in insulin resistance-promoting plasminogen activator inhibitor-1. Accordingly, survivors exhibiting these changes have early signs of clinical metabolic derangement such as increased fasting glucose and hemoglobin A1c.\n\n\nCONCLUSION\nChildhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic subcutaneous adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health.\n\n\nFUNDING\nRockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); anonymous donor (Memorial Sloan Kettering Cancer Center).