Obesity promotes conserved inflammatory and metabolic transcriptional programs in colon tumors: evidence from mouse models and the ColoCare Study Patient Cohort.

BACKGROUND

The 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.

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.