Retinoic Acid Signaling Drives Differentiation towards Enterocytes in Colorectal Cancer

Retinoic Acid (RA) signaling is an important and conserved pathway that regulated cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes homeostasis malignant transformation and disease progression in the intestine, remain incompletely understood. Here, we show that activation of the Retinoic Acid Receptor and the Retinoid X Receptor results in enhanced transcription of enterocyte-specific genes in mouse small intestinal organoids. Conversely, inhibition of this pathway results in reduced expression of genes associated with the absorptive lineage. Strikingly, this latter effect is conserved in a human organoid model for colorectal cancer (CRC) progression. We further show that the epigenome in metastatic organoids is less permissive for RXR binding compared to pre-metastatic organoids, resulting in reduced sensitivity for RA signaling perturbations. Finally, we show that reduced RXR target gene expression correlates with worse CRC prognosis, implying RA signaling as a putative therapeutic strategy in CRC. Overall design: RNA-seq analysis of mouse small intestinal organoids treated with several compounds that affect retinoic acid signaling. RNA-seq analysis of human colorectal cancer organoids treated with several compounds that affect retinoic acid signaling. ATAC-seq of human colorectal cancer organoids with either 3 or 4 prevalent cancer driving mutations.