Retinoic Acid Signaling Drives Differentiation Toward the Absorptive Lineage in Colorectal Cancer

Overview

Journal iScience

Publisher Cell Press

Date 2021 Dec 8

PMID 34877501

Citations 9

Authors

Roelof A Wester

Lisa van Voorthuijsen

Hannah K Neikes

Jelmer J Dijkstra

Lieke A Lamers

Siebren Frolich

Maarten van der Sande

Colin Logie

Rik G H Lindeboom

Michiel Vermeulen

Affiliations

Soon will be listed here.

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.

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