Cargando…

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 tr...

Descripción completa

Detalles Bibliográficos
Autores principales: Wester, Roelof A., van Voorthuijsen, Lisa, Neikes, Hannah K., Dijkstra, Jelmer J., Lamers, Lieke A., Frölich, Siebren, van der Sande, Maarten, Logie, Colin, Lindeboom, Rik G.H., Vermeulen, Michiel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633980/
https://www.ncbi.nlm.nih.gov/pubmed/34877501
http://dx.doi.org/10.1016/j.isci.2021.103444
_version_ 1784608041062105088
author Wester, Roelof A.
van Voorthuijsen, Lisa
Neikes, Hannah K.
Dijkstra, Jelmer J.
Lamers, Lieke A.
Frölich, Siebren
van der Sande, Maarten
Logie, Colin
Lindeboom, Rik G.H.
Vermeulen, Michiel
author_facet Wester, Roelof A.
van Voorthuijsen, Lisa
Neikes, Hannah K.
Dijkstra, Jelmer J.
Lamers, Lieke A.
Frölich, Siebren
van der Sande, Maarten
Logie, Colin
Lindeboom, Rik G.H.
Vermeulen, Michiel
author_sort Wester, Roelof A.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8633980
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-86339802021-12-06 Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer Wester, Roelof A. van Voorthuijsen, Lisa Neikes, Hannah K. Dijkstra, Jelmer J. Lamers, Lieke A. Frölich, Siebren van der Sande, Maarten Logie, Colin Lindeboom, Rik G.H. Vermeulen, Michiel iScience Article 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. Elsevier 2021-11-15 /pmc/articles/PMC8633980/ /pubmed/34877501 http://dx.doi.org/10.1016/j.isci.2021.103444 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wester, Roelof A.
van Voorthuijsen, Lisa
Neikes, Hannah K.
Dijkstra, Jelmer J.
Lamers, Lieke A.
Frölich, Siebren
van der Sande, Maarten
Logie, Colin
Lindeboom, Rik G.H.
Vermeulen, Michiel
Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
title Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
title_full Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
title_fullStr Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
title_full_unstemmed Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
title_short Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
title_sort retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633980/
https://www.ncbi.nlm.nih.gov/pubmed/34877501
http://dx.doi.org/10.1016/j.isci.2021.103444
work_keys_str_mv AT westerroelofa retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT vanvoorthuijsenlisa retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT neikeshannahk retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT dijkstrajelmerj retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT lamersliekea retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT frolichsiebren retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT vandersandemaarten retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT logiecolin retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT lindeboomrikgh retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer
AT vermeulenmichiel retinoicacidsignalingdrivesdifferentiationtowardtheabsorptivelineageincolorectalcancer