Multi-omics Analysis Reveals Adipose–tumor Crosstalk in Patients with Colorectal Cancer

Abstract

◥Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumoradjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelialto-mesenchymal transition-as in fibrosis and metastasisand genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandinendoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted.See related spotlight by Colacino et al., p. 803

Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis

“…The pathophysiological state associated with obesity includes visceral adipose tissue and hepatic dysfunction which leads to systemic insulin resistance and inflammation, the dysregulation of adipokines, and dysbiosis (microbial imbalance) (15,16); all of these pathophysiological alterations have been hypothesized to promote a favorable niche for the pathogenesis of CRC (17)(18)(19)(20)(21). Insulin resistant visceral adipose tissue participates in cross-talk with CRC and promotes a favorable niche by secreting metabolites, growth factors, and proinflammatory cytokines (22)(23)(24). Elevated pro-inflammatory cytokines are associated with an increased risk of CRC, (9,(25)(26)(27)(28) and a circulating inflammatory signature (high miR-21, IL-6, and IL-8) predicts lower progressionfree and overall survival of patients with metastatic CRC (29).…”

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

“…Recent findings from Haffa et al have further shed light that BMI poorly reflects fat mass-associated changes in visceral adipose tissue (VAT) [5]. In contrast to subcutaneous adipose tissue (SAT), we and others have demonstrated that excessive visceral adipose tissue (VAT) is more strongly associated with metabolic perturbations and inflammation [5][6][7][8]. Our prior studies also suggest that VAT secretion of fibroblast growth factor-2 (FGF2) is associated with malignant transformation [9,10].…”

iMAP: A Web Server for Metabolomics Data Integrative Analysis

“…Hydroxyproline is abundant in collagen, and interstitial collagen is a major constituent of the CRC matrix. This may explain the significant change of hydroxyproline observed in CRC patients (Karna et al, 2012 ; Holowatyj et al, 2020 ). Aminolevulinate (also known as 5-aminolevulinic acid or 5ALA) is a precursor to fluorescent protoporphyrin IX.…”