Open Access

Elaine M Glenny, Tengda Lin, Victoria M Bandera, Babak Mirminachi, Saratchandra S Khumukcham, Biljana Gigic, Christy A Warby, Olena Aksonova, Michael F Coleman, Alessandro Carpanese, Calista Busch, Caroline Himbert, Jennifer Ose, David A Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Sheetal Hardikar, Jessica N Cohan, Jolanta Jedrzkiewicz, Alexander Brobeil, Martin A Schneider, Christoph Kahlert, Erin M Siegel, Doratha A Byrd, Adetunji T Toriola, David Shibata, Christopher I Li, Jane C Figueiredo, Aik Choon Tan, Jatin Roper, Cornelia M Ulrich, Stephen D Hursting

• 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 Apcnull KrasG12D/+ Trp53null Smad4null 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 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.