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Inflammatory Stromal Aging in Ulcerative Colitis and Colitis-Associated Cancer
Khalil Almotah1,2, Uyen Tran1, Haylee Gilbert1
1Dept. Cardiovascular & Metabolic Sciences, Cleveland Clinic Research, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195.
Biorxiv : the Preprint Server for Biology
|June 4, 2026
Summary
Colon fibroblasts in ulcerative colitis develop a pro-inflammatory state linked to senescence and epigenetic memory, driving cancer progression. This cellular memory sustains elevated CXCL8 expression, indicating a key role in inflammation-driven colon tumorigenesis.
Area of Science:
- Gastroenterology
- Immunology
- Oncology
Background:
- Ulcerative colitis (UC) is a chronic inflammatory disease.
- Inflammation drives UC progression from dysplasia to colon cancer.
- Fibroblasts in the tumor microenvironment play a critical role.
Purpose of the Study:
- To elucidate the mechanistic link between fibroblast inflammatory signals, microbial infiltration, and cellular memory in colitis.
- To investigate the pro-inflammatory state of interstitial fibroblasts in UC and its role in disease progression.
Main Methods:
- Analysis of primary colon fibroblasts from normal, colitis, and cancer samples.
- In vitro studies and in vivo co-inoculation cancer models.
- mRNA sequencing, NFκB signaling pathway analysis, and iPSC reprogramming.
Main Results:
- Disease-associated fibroblasts exhibit an injury-induced senescence pathway.
- Elevated CXCL8 expression in colitis and cancer fibroblasts is triggered by NFκB signaling.
- Fibroblasts from UC patients retain epigenetic memory, sustaining high CXCL8 expression.
Conclusions:
- The senescence-associated secretory phenotype of colon fibroblasts indicates inflammation-driven colon tumorigenesis.
- Fibroblast epigenetic memory contributes to sustained inflammation and cancer progression in UC.
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