Obesity promotes conserved inflammatory and metabolic transcriptional programs in mouse and human colon tumors
Glenny, E. M.; Lin, T.; Bandera, V. M.; Mirminachi, B.; Khumukcham, S. S.; Gigic, B.; Warby, C. A.; Aksonova, O.; Coleman, M. F.; Carpanese, A.; Busch, C.; Himbert, C.; Ose, J.; Nix, D. A.; Boucher, K.; Schirmacher, P.; Strehli, I.; Hardikar, S.; Cohan, J. N.; Jedrzkiewicz, J.; Brobeil, A.; Schneider, M. A.; Kahlert, C.; Siegel, E. M.; Byrd, D. A.; Toriola, A. T.; Shibata, D.; Li, C. I.; Figueiredo, J. C.; Tan, A. C.; Roper, J.; Ulrich, C. M.; Hursting, S. D.
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BackgroundThe global prevalence of obesity, an established risk and progression factor for colon cancer, is high and rising. Unfortunately, the mechanisms underlying the obesity-colon cancer association are incompletely understood, and new molecular targets enabling more effective intervention strategies to break the obesity-colon cancer link are urgently needed. ObjectiveThis study integrated RNA sequencing data from mouse and human colon tumor samples, as well as human adipose samples, to rigorously establish obesity-associated transcriptomic signatures conserved between the two species. MethodsWe employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc-null;KrasG12D/+;Trp53-null;Smad4-null;tdTomato colon tumor organoids. Epithelial cell adhesion molecule (EpCAM)-positive cells from murine tumors, and 193 human colon tumors and 188 human mesenteric adipose tissue samples from the ColoCare cohort underwent transcriptomic analyses. ResultsDiet-induced obesity reduced survival in the mouse model of colon cancer. Integrated transcriptomic analyses of EpCAM-positive murine tumor cells and bulk human tumors revealed obesity-driven enrichment of inflammation and metabolic pathways, including upregulation of genes involved in innate immune sensing (TLR2, MYD88, IRF4) and tumor microenvironment remodeling (MMP9, TGFB1, SERPINE1). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the ColoCare cohort indicated that obesity amplifies inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions. ConclusionsThese results establish obesity-associated adipose tissue dysregulation as a key inter-tissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.
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