Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids

Samaneh K. Sarvestani, Steven A. Signs, Veronique Lefebvre, Stephen Mack, Ying Ni, Andrew Morton, Ernest R. Chan, Xiaoxia Li, Paul Fox, Angela Ting, Matthew F. Kalady, Michael Cruise, Jean Ashburn, Jennifer Stiene, Wei Lai, David Liska, Shao Xiang, Emina H. Huang

Research output: Contribution to journalArticlepeer-review

Abstract

Ulcerative colitis (UC) is a prevalent form of inflammatory bowel disease (IBD) whose pathogenic mechanisms remain unclear. Elucidating these mechanisms is important to reduce UC symptoms and to prevent UC progression into colitisassociated colon cancer (CAC). Our goal was to develop and validate faithful, humanderived, UC models and analyze them at histologic, transcriptomic and epigenetic levels to allow mechanistic studies of UC and CAC pathogenesis. We generated patient-derived primary-organoid cultures from UC and non-IBD colonic epithelium. We phenotyped them histologically and used next-generationsequencing approaches to profile whole transcriptomes and epigenomes of organoids and primary tissues. Tissue organization and expression of mucin 2 (MUC2) and lysozyme (LYZ) demonstrated histologic faithfulness of organoids to healthy and diseased colonic epithelium. Transcriptomic analyses showed increased expression of inflammatory pathways in UC patient-derived organoids and tissues. Profiling for active enhancers using the H3K27ac histone modification revealed UC-derived organoid enrichment for pathways indicative of gastrointestinal cancer, including S100 calcium-binding protein P (S100P), and revealed novel markers for GI cancer, including both LYZ and neuropeptide S receptor 1 (NPSR1). Immunolocalization showed increased levels of LYZ, S100P, and NPSR1 proteins in UC and CAC.In conclusion, primary colonic organoid cultures from UC and non-IBD patients can be established that faithfully represent diseased or normal colonic states. These models reveal precancerous molecular pathways that are already activated in UC. The findings demonstrate the suitability of primary organoids for dissecting UC and CAC pathogenic mechanisms and suggest new targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)28717-28730
Number of pages14
JournalOncotarget
Volume9
Issue number47
DOIs
StatePublished - Jun 19 2018
Externally publishedYes

Keywords

  • Colitis associated cancer
  • H3K27Ac enhancer chromatin mark
  • Inflammation
  • Organoids
  • Ulcerative colitis

ASJC Scopus subject areas

  • Oncology

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