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 c
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.
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Metadaten
Author:Birgitta Elisabeth Michels, Mohammed Hossameldin Mosa, Britta Moyo Grebbin, Diego Yepes, Tahmineh Darvishi, Johannes Hausmann, Henning Urlaub, Stefan Zeuzem, Hans Michael Kvasnicka, Thomas Oellerich, Henner Farin
URN:urn:nbn:de:hebis:30:3-544866
DOI:http://dx.doi.org/10.1084/jem.20180823
ISSN:1540-9538
ISSN:1540-9358
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=30792186
Parent Title (English):Journal of experimental medicine
Publisher:Rockefeller Univ. Press
Place of publication:New York, NY
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/02/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/05/18
Volume:216
Issue:3
Pagenumber:17
First Page:704
Last Page:720
Note:
© 2019 Michels et al. 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/).
HeBIS PPN:465980627
Institutes:Biowissenschaften
Medizin
Georg-Speyer-Haus
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen

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