Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.
Animals
Carcinogenesis
Cell Transformation, Neoplastic
Colonic Neoplasms
/ metabolism
DNA-Binding Proteins
/ genetics
Female
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Homeostasis
Humans
Intestinal Mucosa
/ metabolism
Intestines
/ pathology
Mice
Mice, Inbred C57BL
Neoplasm Proteins
/ genetics
Neoplastic Stem Cells
Oncogenes
Receptors, G-Protein-Coupled
/ metabolism
Transcription Factors
/ genetics
Wnt Proteins
/ metabolism
Wnt Signaling Pathway
beta Catenin
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 02 2019
13 02 2019
Historique:
received:
13
06
2018
accepted:
16
01
2019
entrez:
15
2
2019
pubmed:
15
2
2019
medline:
12
4
2019
Statut:
epublish
Résumé
Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.
Identifiants
pubmed: 30760720
doi: 10.1038/s41467-019-08586-3
pii: 10.1038/s41467-019-08586-3
pmc: PMC6374445
doi:
Substances chimiques
BCL9 protein, human
0
BCL9L protein, human
0
CTNNB1 protein, human
0
DNA-Binding Proteins
0
LGR5 protein, human
0
Neoplasm Proteins
0
Receptors, G-Protein-Coupled
0
Transcription Factors
0
Wnt Proteins
0
beta Catenin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
723Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : European Research Council
ID : 311301
Pays : International
Commentaires et corrections
Type : ErratumIn
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