Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas.
Details
Serval ID
serval:BIB_4CC88CEB1BCE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas.
Journal
Science advances
ISSN
2375-2548 (Electronic)
ISSN-L
2375-2548
Publication state
Published
Issued date
19/11/2021
Peer-reviewed
Oui
Volume
7
Number
47
Pages
eabj0512
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
[Figure: see text].Somatic mutations in APC or CTNNB1 genes lead to aberrant Wnt signaling and colorectal cancer (CRC) initiation and progression via-catenin-T cell factor/lymphoid enhancer binding factor TCF/LEF transcription factors. We found that Lef1 was expressed exclusively in Apc-mutant, Wnt ligand-independent tumors, but not in ligand-dependent, serrated tumors. To analyze Lef1 function in tumor development, we conditionally deleted Lef1 in intestinal stem cells of Apc(fl/fl) mice or broadly from the entire intestinal epithelium of Apc(fl/fl) or Apc(Min/+) mice. Loss of Lef1 markedly increased tumor initiation and tumor cell proliferation, reduced the expression of several Wnt antagonists, and increased Myc proto-oncogene expression and formation of ectopic crypts in Apc-mutant adenomas. Our results uncover a previously unknown negative feedback mechanism in CRC, in which ectopic Lef1 expression suppresses intestinal tumorigenesis by restricting adenoma cell dedifferentiation to a crypt-progenitor phenotype and by reducing the formation of cancer stem cell niches.
Pubmed
Web of science
Open Access
Yes
Create date
03/12/2021 12:34
Last modification date
23/11/2022 7:10