Browsing by Subject "WNT PATHWAY"

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  • Heino, Sarika; Fang, Shentong; Lähde, Marianne; Högström, Jenny; Nassiri, Sina; Campbell, Andrew; Flanagan, Dustin; Raven, Alexander; Hodder, Michael; Nasreddin, Nadia; Xue, Hai-Hui; Delorenzi, Mauro; Leedham, Simon; Petrova, Tatiana; Sansom, Owen; Alitalo, Kari (2021)
    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.