Abstract
Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though interindividual 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. Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3 mM ASA or vehicle control for 24 h. Gene expression was assessed by RNA-seq, and differentially responsive genes were 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. Apoptosis and necrosis assays were performed, and apoptosis gene expression was measured in organoids. Overall, 8,343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (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 the identification of significant differential responses of apoptotic genes to ASA. 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.NEW & NOTEWORTHY Aspirin treatment in colonic organoids from diverse individuals revealed significant transcriptome-wide responses, especially for genes in lipid and apoptosis signaling pathways. In normal organoids, apoptosis was induced by aspirin, providing one possible mechanism of colorectal cancer chemoprevention. Our results are a first step toward implementation of personalized medicine for aspirin in colorectal cancer prevention.