Human colon organoids reveal distinct physiologic and oncogenic Wnt responses

The Journal of Experimental Medicine
Birgitta E MichelsHenner F Farin

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.

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Citations

Sep 12, 2019·RNA·Muhammad IdrisDavid M Virshup
Jul 15, 2020·The Journal of Clinical Investigation·Catherine OleschAndreas Weigert
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Datasets Mentioned

BETA
GSM2139719
GSM2139725
GSE14333
GSE39582
GSE80981
GSE125578
PXD012650

Methods Mentioned

BETA
PCA
ICE
GTPase
biopsies
FACS
flow cytometry
transfection
PCR

Software Mentioned

HUSAR
R package biomaRt
PROGgeneV2
biomaRt
cBioPortal for genomics
RStudio
Aperio eSlide Manager
gplots
Rtoolbox
GEO2R

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