Abstract A171: Using patient-derived colorectal organoids to explore IL-6-driven mechanisms of colorectal carcinogenesis

Abstract

Abstract Colorectal cancer (CRC) remains the leading cause of cancer death among men and women in Puerto Rico. In patients below age 50, CRC mortality is increasing three times faster in Puerto Rican and mainland Hispanics than in the United States overall. This data highlights a growing health disparity that warrants further investigation. CRC risk is shaped by interactions between environmental exposures, sociocultural behaviors and genetic suceptibility. However, how Puerto Rico’s unique exposome interacts with genetic susceptibility to promote CRC remains unknown. Preliminary data shows that interleukin-6 (IL-6), a pro-inflammatory cytokine implicated in colorectal carcinogenesis, may be differentially regulated in Hispanics. Specifically, more than 70% of Puerto Rican Hispanic samples carry an IL6 -174G>C promoter variant, which may heighten inflammatory responses to regional exposures. Here, we investigated whether the IL6 promoter variant modulates inflammatory responses to enviromental stimuli using patient-derived organoids (PDOs). Peripheral blood leukocytes were used for IL6 genotyping and plasma IL-6 was quantified using ELISA. Colorectal PDOs exposed to IL-6 were assessed for IL-6/JAK/STAT3 activation by Western blot. Genotype-stratified PDOs were exposed to palmitic acid (PA), a diet-associated exposure, or lipopolysaccharide (LPS), a microbiome-associated exposure, and evaluated for inflammatory signaling by immunostaining and ELISA. Pro-inflammatory CG/GG genotypes were more common among CRC cases than controls and were associated with higher circulating IL-6 levels than the CC genotype. In colorectal PDOs, IL-6 treatment increased IL-6/JAK/STAT3 activation, shown by elevated phospho-STAT3 and antiapoptotic Bcl-2 protein levels. Variant PDOs exposed to PA or LPS had increased nuclear pSTAT3, and higher secreted IL-6 levels as shown by ELISA. These results suggest that the IL6 -174G>C promoter variant may heighten inflammatory responses to diet- and microbiome–associated exposures by increasing IL-6/JAK/STAT3 signaling. This data supports gene-environment interactions that may contribute to IL-6-driven colorectal carcinogenesis in Puerto Rico. Further research is needed to determine whether the IL6 -174G>C promoter variant is a direct contributor to the increasing CRC health disparities observed among Hispanics. Citation Format: Selene Schiavone-Chamorro, Luis D. Borrero-García, Kimberly Lopez-Rivera, Fabian Santiago-Rodríguez, Edelis Rosado-Agosto, Camille Montalvo-Pacheco, Adbiel Rodríguez-Santiago, Leslie Casiano, Joel Gabre, María González-Pons. Using patient-derived colorectal organoids to explore IL-6-driven mechanisms of colorectal carcinogenesis [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr A171.