| First Author | Heino S | Year | 2021 |
| Journal | Sci Adv | Volume | 7 |
| Issue | 47 | Pages | eabj0512 |
| PubMed ID | 34788095 | Mgi Jnum | J:315124 |
| Mgi Id | MGI:6830821 | Doi | 10.1126/sciadv.abj0512 |
| Citation | Heino S, et al. (2021) Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas. Sci Adv 7(47):eabj0512 |
| abstractText | Somatic mutations in APC or CTNNB1 genes lead to aberrant Wnt signaling and colorectal cancer (CRC) initiation and progression via-cateninâT cell factor/lymphoid enhancer binding factor TCF/LEF transcription factors. We found that Lef1 was expressed exclusively in Apc-mutant, Wnt ligandâindependent tumors, but not in ligand-dependent, serrated tumors. To analyze Lef1 function in tumor development, we conditionally deleted Lef1 in intestinal stem cells of Apcfl/fl mice or broadly from the entire intestinal epithelium of Apcfl/fl or ApcMin/+ 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. |
