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J Exp Med. 2019 Mar 4;216(3):704-720. doi: 10.1084/jem.20180823. Epub 2019 Feb 21.

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses.

Michels BE1,2,3,4,5, Mosa MH1,2,3,4, Grebbin BM1,2,3,4, Yepes D1,3,6, Darvishi T1,2,3, Hausmann J7, Urlaub H8,9, Zeuzem S7, Kvasnicka HM10, Oellerich T1,3,4,6, Farin HF11,2,3,4.

Author information

1
German Cancer Consortium, Germany.
2
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
3
German Cancer Research Center, Heidelberg, Germany.
4
Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.
5
Faculty of Biological Sciences, Goethe University, Frankfurt am Main, Germany.
6
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany.
7
Department of Internal Medicine I, Gastroenterology, Goethe University, Frankfurt am Main, Germany.
8
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
9
Institute for Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
10
Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
11
German Cancer Consortium, Germany farin@gsh.uni-frankfurt.de.

Abstract

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.

PMID:
30792186
PMCID:
PMC6400532
[Available on 2019-09-04]
DOI:
10.1084/jem.20180823

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