Genomic and cellular responses to aspirin in colonic organoids from African- and European-Americans.

Abstract

Background: Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though inter-individual responses and cellular mechanisms are not well characterized. Human organoids are ideal to study treatment responses across individuals. Here, colonic organoids from African-Americans (AA) and European-Americans (EA)were used to profile genomic and cellular ASA responses. Methods: Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3mM ASA or vehicle control for 24h. Gene expression was assessed by RNA-seq, and differentially responsive genes analyzed by condition, population and for gene set enrichment. Top differentially responsive genes were assessed by time and ASA doses in independent organoids. Expression quantitative trait loci (eQTL) mapping was performed to identify variants associated with condition-specific responses. Proliferation, apoptosis and necrosis assays were performed, and apoptosis gene expression measured in organoids. Results: Overall, 8343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and PPAR signaling was found. Significant treatment eQTLs were identified for relevant genes involved in FAO, apoptosis and prostaglandin metabolism. ASA-induced apoptosis and secondary necrosis were confirmed with identification of significant differential responses of apoptotic genes to ASA. Conclusions: Results demonstrate large transcriptional responses to ASA treatment with differences in responses between individuals. Genomic and cellular results suggest that ASA effects on the mitochondria are key mechanisms of action that could underlie clinical effects. These results could be used to assess clinical treatment responses for chemoprevention in the future.