Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34788095.
- Also identified by DOI 10.1126/sciadv.abj0512 and PMC identifier 8598008.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Somatic mutations in <i>APC</i> or <i>CTNNB1</i> 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 <i>Lef1</i> was expressed exclusively in <i>Apc</i>-mutant, Wnt ligand–independent tumors, but not in ligand-dependent, serrated tumors. To analyze <i>Lef1</i> function in tumor development, we conditionally deleted <i>Lef1</i> in intestinal stem cells of <i>Apc<sup>fl/fl</sup></i> mice or broadly from the entire intestinal epithelium of <i>Apc<sup>fl/fl</sup></i> or <i>Apc<sup>Min/+</sup></i> mice. Loss of <i>Lef1</i> markedly increased tumor initiation and tumor cell proliferation, reduced the expression of several Wnt antagonists, and increased <i>Myc</i> proto-oncogene expression and formation of ectopic crypts in <i>Apc</i>-mutant adenomas. Our results uncover a previously unknown negative feedback mechanism in CRC, in which ectopic <i>Lef1</i> expression suppresses intestinal tumorigenesis by restricting adenoma cell dedifferentiation to a crypt-progenitor phenotype and by reducing the formation of cancer stem cell niches.