Inflammatory Stromal Aging in Ulcerative Colitis and Colitis-Associated Cancer

ABSTRACTUlcerative colitis is a chronic inflammatory bowel disease that can progress from dysplasia to cancer. Inflammatory responses are critical drivers in this process, typically triggered by epithelial lesions and the ensuing infiltration of microbiota into the interstitial layer. Here, we focus on the pro-inflammatory state of the interstitial fibroblasts, which promotes immune infiltration and augments disease progression. The study aims to provide a mechanistic link how fibroblasts of the colitis-associated microenvironment integrate inflammatory signals, microbial infiltration and cellular memory. To this end, we investigated a large number of primary colon fibroblasts obtained from normal, colitis and colon cancer samples using a range of in vitro approaches and an in vivo co-inoculation cancer model. mRNA sequencing analysis identified that the disease-associated fibroblasts are exhibit a cellular inflammatory status, which involves the injury-induced senescence pathway. Using CXCL8, a potent chemokine upregulated in colitis and cancer colon fibroblasts, as a paradigm, this inflammatory status is triggered by the activation of the NF{kappa}B signaling via immune-derived cytokines (TNF, IL-1{beta}), bacterial signals (LPS) and the microbiome itself using mycoplasma as a paradigm. Finally, iPSC reprogramming studies indicate that fibroblasts from ulcerative colitis retain an epigenetic memory that sustains elevated CXCL8 expression. Together, our findings demonstrate that the senescence associated secretory phenotype of colon fibroblasts is a robust indicator for inflammation-driven colon tumorigenesis.