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

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 (hOEC867) linked to cancer, tumor morphology, and metabolism similar to those in the colon of high-fat-diet obese mice. The hOEC867signature represented pathways found in human colon cancer. In unsupervised clustering, hOEC867separated 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. Comparative gene expression profiling analysis of RNA-seq data for HT29 cells treated with conditioned media from ESC-only MPS and obese EPAT MPS

肥胖流行与结直肠癌（colorectal cancer, CRC）的发病风险升高及病情进展密切相关，但其具体调控机制仍未明确。在肥胖个体中，附着于结肠的肥大网膜脂肪组织（epiploic adipose tissue, EPAT）与其他脂肪组织相比具有独特的生物学特性。我们提出假说：这种尚未被充分研究的脂肪组织可作为促肿瘤组织，并据此开发了一种新型的人源EPAT依赖性结直肠癌微生理系统（CRC-MPS）。在CRC-MPS模型中，与瘦体型个体的EPAT不同，肥胖个体的EPAT可显著招募结肠癌细胞HT29-GFP并促进其增殖。肥胖CRC-MPS的条件培养基（conditioned media, CM）可显著提升HT29与HCT116细胞的增殖与迁移能力（p<0.001）。在HT29细胞中，该条件培养基可诱导与癌症、肿瘤形态及代谢相关的差异基因表达特征hOEC867，该特征与高脂饮食肥胖小鼠结肠组织中的基因表达谱高度相似。hOEC867特征涵盖了人类结直肠癌中已发现的信号通路。在无监督聚类分析中，hOEC867可显著区分结直肠癌样本与正常样本的转录组（主成分分析，PCA，p=9.6×10^−11）。经条件培养基处理的HT29细胞中验证的差异基因（p<0.05）可调控细胞周期、癌症干细胞、甲基化及转移过程，且在人类结直肠癌（The Cancer Genome Atlas, TCGA）数据集内亦存在类似的表达改变。本研究揭示了肥胖状态下EPAT在结直肠癌中的促肿瘤作用，并为探索结直肠癌的关键发病机制、开发有效治疗手段提供了标准化研究平台。对分别用仅含胚胎干细胞（embryonic stem cell, ESC）的MPS条件培养基与肥胖EPAT MPS条件培养基处理的HT29细胞的RNA测序数据进行比较基因表达谱分析。