Cargando…
Human colon organoids reveal distinct physiologic and oncogenic Wnt responses
Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancer (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiological Wnt activity, we have p...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400532/ https://www.ncbi.nlm.nih.gov/pubmed/30792186 http://dx.doi.org/10.1084/jem.20180823 |
_version_ | 1783399976093614080 |
---|---|
author | Michels, Birgitta E. Mosa, Mohammed H. Grebbin, Britta M. Yepes, Diego Darvishi, Tahmineh Hausmann, Johannes Urlaub, Henning Zeuzem, Stefan Kvasnicka, Hans M. Oellerich, Thomas Farin, Henner F. |
author_facet | Michels, Birgitta E. Mosa, Mohammed H. Grebbin, Britta M. Yepes, Diego Darvishi, Tahmineh Hausmann, Johannes Urlaub, Henning Zeuzem, Stefan Kvasnicka, Hans M. Oellerich, Thomas Farin, Henner F. |
author_sort | Michels, Birgitta E. |
collection | PubMed |
description | Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancer (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiological Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9-induced APC loss. We could catalog two nonoverlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC. |
format | Online Article Text |
id | pubmed-6400532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-64005322019-09-04 Human colon organoids reveal distinct physiologic and oncogenic Wnt responses Michels, Birgitta E. Mosa, Mohammed H. Grebbin, Britta M. Yepes, Diego Darvishi, Tahmineh Hausmann, Johannes Urlaub, Henning Zeuzem, Stefan Kvasnicka, Hans M. Oellerich, Thomas Farin, Henner F. J Exp Med Research Articles Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancer (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiological Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9-induced APC loss. We could catalog two nonoverlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC. Rockefeller University Press 2019-03-04 /pmc/articles/PMC6400532/ /pubmed/30792186 http://dx.doi.org/10.1084/jem.20180823 Text en © 2019 Michels et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Michels, Birgitta E. Mosa, Mohammed H. Grebbin, Britta M. Yepes, Diego Darvishi, Tahmineh Hausmann, Johannes Urlaub, Henning Zeuzem, Stefan Kvasnicka, Hans M. Oellerich, Thomas Farin, Henner F. Human colon organoids reveal distinct physiologic and oncogenic Wnt responses |
title | Human colon organoids reveal distinct physiologic and oncogenic Wnt responses |
title_full | Human colon organoids reveal distinct physiologic and oncogenic Wnt responses |
title_fullStr | Human colon organoids reveal distinct physiologic and oncogenic Wnt responses |
title_full_unstemmed | Human colon organoids reveal distinct physiologic and oncogenic Wnt responses |
title_short | Human colon organoids reveal distinct physiologic and oncogenic Wnt responses |
title_sort | human colon organoids reveal distinct physiologic and oncogenic wnt responses |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400532/ https://www.ncbi.nlm.nih.gov/pubmed/30792186 http://dx.doi.org/10.1084/jem.20180823 |
work_keys_str_mv | AT michelsbirgittae humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT mosamohammedh humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT grebbinbrittam humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT yepesdiego humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT darvishitahmineh humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT hausmannjohannes humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT urlaubhenning humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT zeuzemstefan humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT kvasnickahansm humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT oellerichthomas humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses AT farinhennerf humancolonorganoidsrevealdistinctphysiologicandoncogenicwntresponses |