Therapeutic radiation exposure of the abdomen during childhood induces chronic adipose tissue dysfunction
Xiaojing Huang, Olivia A. Maguire, Jeanne M. Walker, Caroline S. Jiang, Thomas S. Carroll, Ji-Dung Luo, Emily Tonorezos, Danielle Novetsky Friedman, Paul Cohen
Xiaojing Huang, Olivia A. Maguire, Jeanne M. Walker, Caroline S. Jiang, Thomas S. Carroll, Ji-Dung Luo, Emily Tonorezos, Danielle Novetsky Friedman, Paul Cohen
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Clinical Research and Public Health Metabolism Oncology

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

Abstract

BACKGROUND Childhood 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.METHODS We 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 s.c. adipose biopsies to obtain tissue for bulk RNA sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.RESULTS Irradiated 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.CONCLUSION Childhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic s.c. adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health.FUNDING This study was supported by Rockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1 TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); and an anonymous donor (MSKCC).

Authors

Xiaojing Huang, Olivia A. Maguire, Jeanne M. Walker, Caroline S. Jiang, Thomas S. Carroll, Ji-Dung Luo, Emily Tonorezos, Danielle Novetsky Friedman, Paul Cohen

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Figure 4

Cell type deconvolution.

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Cell type deconvolution. (A) UMAP of Seurat clustering of SAT cells from...
(A) UMAP of Seurat clustering of SAT cells from Vijay et al. (25). p, progenitor; m, myeloid; t, T cell; b, B cell; e, endothelial clusters. (B) CIBERSORTx deconvolution of bulk RNA-seq data using signature matrix derived from clusters in A. (C) Subclustering of m1 and m2 macrophage populations. (D) Deconvolution using signature matrix with m1 and m2 clusters expanded to the subclusters identified in C. Differences among groups in B were tested using repeated-measures ANOVA after aligned rank transformation, which showed significant interaction between group and cell type (P = 0.0003). FDR-adjusted P values for post hoc pairwise comparisons were calculated using estimated marginal means on only group comparisons within each cell type, not all possible pairwise comparisons within the data. Differences among groups in D were tested using the Kruskal-Wallis test, followed by the Dunn test for post hoc comparisons with FDR adjustment. #P < 0.05, ##P < 0.01 on post hoc pairwise comparisons without FDR adjustment; *P < 0.05, **P < 0.01 on post hoc pairwise comparisons with FDR adjustment. Data are shown as mean ± SD.