Abstract 5430: Discovery of CYP26A1 as a link between WNT and retinoic acid signaling pathways that modulates retinoid-induced differentiation of APC-mutant colorectal cancer cells

Abstract

Abstract APC mutation is the main driver mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. We hypothesize that a functional link exists between WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induced wt-APC expression in APC-mutant CRC cells and assessed the ability of all-trans-retinoic acid (ATRA) to induce differentiation. Notably, ATRA substantially increased expression of the WNT-target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, RA and WNT pathways crosstalk to modulate CYP26A1 metabolism of retinoids and retinoid agents. We found that inducing wt-APC augments ATRA-induced cell differentiation by: i) decreasing cell proliferation; ii) suppressing ALDH1A1 expression; iii) decreasing ALDH+ SCs; and iv) increasing neuroendocrine cell differentiation. NanoString profiling and bioinformatics also identified a novel CYP26A1-based network that links WNT and RA signaling. Moreover, in an effort to translate manipulation of the WNT/RA imbalance as a therapeutic approach in vitro, we treated HT29, SW480, and HCT116 CRC cells with inhibitors against CYP26A1 enzyme activity and WNT signaling. We found that CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Furthermore, decreased CYP26A1 expression in tumor vs normal tissue was determined to be a predictor of patient survival in patients who have wt-APC. Thus, by inducing wt-APC expression and exogenously activating RA signaling, we found a way to increase differentiation of SCs along the NEC (and other) lineage(s). Translating this strategy in vivo might lead to new, more effective treatments involving retinoids for CRC patients. Citation Format: Caroline O. Facey, Victoria O. Hunsu, Chi Zhang, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Discovery of CYP26A1 as a link between WNT and retinoic acid signaling pathways that modulates retinoid-induced differentiation of APC-mutant colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5430.