A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 12 2019
02 12 2019
Historique:
received:
04
02
2019
accepted:
04
11
2019
entrez:
4
12
2019
pubmed:
4
12
2019
medline:
5
3
2020
Statut:
epublish
Résumé
Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers.
Identifiants
pubmed: 31792216
doi: 10.1038/s41467-019-13330-y
pii: 10.1038/s41467-019-13330-y
pmc: PMC6889384
doi:
Substances chimiques
R-spondin3 protein, mouse
0
Thrombospondins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5490Subventions
Organisme : NCI NIH HHS
ID : K22 CA212058
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA173245
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA209923
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA191198
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD040372
Pays : United States
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