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19 novembre 2021
- doi: 10.1126/sciadv.abj0512
- issn: 2375-2548
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info:eu-repo/semantics/altIdentifier/doi/10.1126/sciadv.abj0512
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info:eu-repo/semantics/altIdentifier/pmid/34788095
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_4CC88CEB1BCE2
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S. Heino et al., « Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas. », Serveur académique Lausannois, ID : 10.1126/sciadv.abj0512
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[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.