Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: evidence from mouse models and the ColoCare Study Patient Cohort.
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Glenny Elaine M, Lin Tengda, Bandera Victoria M, Mirminachi Babak, Khumukcham Saratchandra S, Gigic Biljana, Warby Christy A, Aksonova Olena, Coleman Michael F, Carpanese Alessandro, Busch Calista, Himbert Caroline, Ose Jennifer, Nix David A, Boucher Kenneth, Schirmacher Peter, Strehli Ildiko, Hardikar Sheetal, Cohan Jessica N, Jedrzkiewicz Jolanta, Brobeil Alexander, Schneider Martin A, Kahlert Christoph, Siegel Erin M, Byrd Doratha A, Toriola Adetunji T, Shibata David, Li Christopher I, Figueiredo Jane C, Tan Aik Choon, Roper Jatin, Ulrich Cornelia M, Hursting Stephen D
Аннотация
OBJECTIVES: This 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 2 species.
METHODS: We employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic ApcnullKrasG12D/+Trp53nullSmad4nulltdTomato 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 prospective ColoCare Study cohort underwent transcriptomic analyses.
RESULTS: Diet-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 the upregulation of genes involved in innate immune sensing (TLR2, MYD88, and IRF4) and tumor microenvironment remodeling (MMP9, TGFB1, and SERPINE1). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the study patients (63 ± 13 y, 48% female, body mass index 28.9 ± 6.0 kg/m2) indicated that obesity was associated with enriched inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions.
CONCLUSIONS: These results establish obesity-associated adipose tissue dysregulation as a key intertissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.