Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

作者：Emilie Abby, Stefan C. Dentro, Michael Hall, Joanna C. Fowler, Swee Hoe Ong, Roshan Sood, Albert Herms, Gabriel Piedrafita, Irina Abnizova, Christian W. Siebel, Moritz Gerstung, Benjamin A. Hall, Philip H. Jones · 发表于：Nature Genetics · 年份：2023 · DOI：10.1038/s41588-022-01280-z · 被引用次数：124 · 研究领域：Developmental Biology and Gene Regulation、Renal and related cancers、Cancer Cells and Metastasis

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.