Human colon organoids reveal distinct physiologic and oncogenic Wnt responses.
J Exp Med
; 216(3): 704-720, 2019 03 04.
Article
em En
| MEDLINE
| ID: mdl-30792186
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Mortalidade
/
Geral
/
Tipos_de_cancer
/
Colon_e_reto
Base de dados:
MEDLINE
Assunto principal:
Organoides
/
Colo
/
Neoplasias do Colo
/
Via de Sinalização Wnt
Limite:
Humans
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha