Obesity promotes conserved inflammatory and metabolic transcriptional programs in mouse and human colon tumors

Abstract

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.

Objective: 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 two species.

Methods: We 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.

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 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.

Conclusions: These 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.