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

Roelof A Wester; Lisa van Voorthuijsen; Hannah K Neikes; Jelmer J Dijkstra; Lieke A Lamers; Siebren Frölich; Maarten van der Sande; Colin Logie; Rik G H Lindeboom; Michiel Vermeulen

doi:10.1016/j.isci.2021.103444

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

iScience. 2021 Nov 15;24(12):103444. doi: 10.1016/j.isci.2021.103444. eCollection 2021 Dec 17.

Affiliations

¹ Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, 6525GA Nijmegen, the Netherlands.
² Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen, 6525GA Nijmegen, the Netherlands.
³ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Abstract

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.

Keywords: Biological sciences; Cancer; Cell biology; Functional aspects of cell biology; Oncology.