Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas.

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Version: Final published version
License: CC BY 4.0
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
Author(s)
Heino S., Fang S., Lähde M., Högström J., Nassiri S., Campbell A., Flanagan D., Raven A., Hodder M., Nasreddin N., Xue H.H., Delorenzi M., Leedham S., Petrova T.V., Sansom O., Alitalo K.
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
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
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