Epiploic Adipose Tissue (EPAT) in Obese Individuals Promotes Colonic Tumorigenesis: A Novel Model for EPAT-Dependent Colorectal Cancer Progression

SIMPLE SUMMARY: The role of epiploic adipose tissue (EPAT), understudied fat appendages attached to the colon, in obesity-facilitated colorectal cancer (CRC) is unexamined. In our novel microphysiological system, EPAT obtained from obese individuals, unlike EPAT from lean, attracts colon cancer cells’ intrusion and enhances their migration and growth. Conditioned media from this model mediated gene expression in colon cancer cells that are linked to metabolic and tumorigenic remodeling. This EPAT-mediated transcriptional signature defines transcriptomes of human colon cancer. These findings highlight a tumor-promoting role of EPAT, a metabolic tissue, in the colon of obese individuals and establishes a platform for exploration of involved mechanisms and development of effective treatments. ABSTRACT: The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied fat could serve as a tumor-promoting tissue and developed a novel microphysiological system (MPS) for human EPAT-dependent colorectal cancer (CRC-MPS). In CRC-MPS, obese EPAT, unlike lean EPAT, considerably attracted colon cancer HT29-GFP cells and enhanced their growth. Conditioned media (CM) from the obese CRC-MPS significantly increased the growth and migration of HT29 and HCT116 cells (p < 0.001). In HT29 cells, CM stimulated differential gene expression (hOEC(867)) linked to cancer, tumor morphology, and metabolism similar to those in the colon of high-fat-diet obese mice. The hOEC(867) signature represented pathways found in human colon cancer. In unsupervised clustering, hOEC(867) separated transcriptomes of colon cancer samples from normal with high significance (PCA, p = 9.6 × 10(−11)). These genes, validated in CM-treated HT29 cells (p < 0.05), regulate the cell cycle, cancer stem cells, methylation, and metastasis, and are similarly altered in human colon cancer (TCGA). These findings highlight a tumor-promoting role of EPAT in CRC facilitated with obesity and establishes a platform to explore critical mechanisms and develop effective treatments.