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

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dc.contributor.author Heino, Sarika
dc.contributor.author Fang, Shentong
dc.contributor.author Lähde, Marianne
dc.contributor.author Högström, Jenny
dc.contributor.author Nassiri, Sina
dc.contributor.author Campbell, Andrew
dc.contributor.author Flanagan, Dustin
dc.contributor.author Raven, Alexander
dc.contributor.author Hodder, Michael
dc.contributor.author Nasreddin, Nadia
dc.contributor.author Xue, Hai-Hui
dc.contributor.author Delorenzi, Mauro
dc.contributor.author Leedham, Simon
dc.contributor.author Petrova, Tatiana
dc.contributor.author Sansom, Owen
dc.contributor.author Alitalo, Kari
dc.date.accessioned 2021-12-14T07:14:02Z
dc.date.available 2021-12-14T07:14:02Z
dc.date.issued 2021-11
dc.identifier.citation 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
dc.identifier.other PURE: 171239642
dc.identifier.other PURE UUID: e45fe007-aa94-4bfb-9086-bd4094267197
dc.identifier.other WOS: 000720347400013
dc.identifier.uri http://hdl.handle.net/10138/337427
dc.description.abstract 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. en
dc.format.extent 18
dc.language.iso eng
dc.relation.ispartof Science Advances
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject STEM-CELLS
dc.subject TRANSCRIPTION FACTOR
dc.subject BETA-CATENIN
dc.subject C-MYC
dc.subject RIBOSOMAL DNA
dc.subject MICE LACKING
dc.subject COLON-CANCER
dc.subject WNT PATHWAY
dc.subject EXPRESSION
dc.subject APC
dc.subject 3111 Biomedicine
dc.title Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas en
dc.type Article
dc.contributor.organization CAN-PRO - Translational Cancer Medicine Program
dc.contributor.organization Digital Precision Cancer Medicine (iCAN)
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.contributor.organization HUSLAB
dc.contributor.organization Kari Alitalo / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1126/sciadv.abj0512
dc.relation.issn 2375-2548
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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