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

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http://hdl.handle.net/10138/337427

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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 , Sansom , O & Alitalo , K 2021 , ' Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas ' , Science Advances , vol. 7 , no. 47 , 0512 . https://doi.org/10.1126/sciadv.abj0512

Titel: Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas
Författare: 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
Upphovmannens organisation: CAN-PRO - Translational Cancer Medicine Program
Digital Precision Cancer Medicine (iCAN)
Helsinki Institute of Life Science HiLIFE
HUSLAB
Kari Alitalo / Principal Investigator
Datum: 2021-11
Språk: eng
Sidantal: 18
Tillhör serie: Science Advances
ISSN: 2375-2548
DOI: https://doi.org/10.1126/sciadv.abj0512
Permanenta länken (URI): http://hdl.handle.net/10138/337427
Abstrakt: 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.
Subject: STEM-CELLS
TRANSCRIPTION FACTOR
BETA-CATENIN
C-MYC
RIBOSOMAL DNA
MICE LACKING
COLON-CANCER
WNT PATHWAY
EXPRESSION
APC
3111 Biomedicine
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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