Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer

Retinoic acid (RA) signaling is an important and conserved pathway that regulates cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes to homeostasis, malignant transformation, and disease progression in the intestine remain incompletely understood. Here, we report, in agreement with previous findings, 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 RXR motif accessibility depends on progression state of CRC organoids. Finally, we show that reduced RXR target gene expression correlates with worse CRC prognosis, implying RA signaling as a putative therapeutic target in CRC.

Automated summary

Retinoic acid (RA) signaling pathway plays a crucial role in regulating cellular proliferation and differentiation, with perturbations in this pathway implicated in cancer initiation and progression, particularly in the intestine. The activation of Retinoic Acid Receptor and Retinoid X Receptor enhances the transcription of enterocyte-specific genes, while its inhibition results in reduced expression of genes associated with the absorptive lineage, a conserved effect in a human organoid model for colorectal cancer (CRC) progression. Moreover, decreased expression of RXR target genes correlates with poorer CRC prognosis, suggesting RA signaling as a potential therapeutic target in CRC.